Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

RNA-binding proteins and their role in kidney disease

Nature Reviews Nephrology volume 18, pages 153–170 (2022)Cite this article

Subjects

Abstract

RNA-binding proteins (RBPs) are of fundamental importance for post-transcriptional gene regulation and protein synthesis. They are required for pre-mRNA processing and for RNA transport, degradation and translation into protein, and can regulate every step in the life cycle of their RNA targets. In addition, RBP function can be modulated by RNA binding. RBPs also participate in the formation of ribonucleoprotein complexes that build up macromolecular machineries such as the ribosome and spliceosome. Although most research has focused on mRNA-binding proteins, non-coding RNAs are also regulated and sequestered by RBPs. Functional defects and changes in the expression levels of RBPs have been implicated in numerous diseases, including neurological disorders, muscular atrophy and cancers. RBPs also contribute to a wide spectrum of kidney disorders. For example, human antigen R has been reported to have a renoprotective function in acute kidney injury (AKI) but might also contribute to the development of glomerulosclerosis, tubulointerstitial fibrosis and diabetic kidney disease (DKD), loss of bicaudal C is associated with cystic kidney diseases and Y-box binding protein 1 has been implicated in the pathogenesis of AKI, DKD and glomerular disorders. Increasing data suggest that the modulation of RBPs and their interactions with RNA targets could be promising therapeutic strategies for kidney diseases.

Key points

  • The human genome contains more than 1,000 RNA-binding proteins (RBPs), which are involved in every step of the RNA life cycle and have a major impact on cellular biology.

  • RBPs have been shown to have roles in tubular and glomerular kidney diseases, including acute kidney injury (AKI), chronic kidney disease, kidney fibrosis, polycystic kidney disease (PKD), diabetic kidney disease and glomerulonephritis.

  • RBPs can have both protective and pathogenic roles in kidney diseases; for example, two of the best studied RBPs — HuR and YBX1 — ameliorate damage in AKI but promote kidney fibrosis.

  • The role of RBPs in kidney disorders is conserved throughout evolution; for example, mutations in BICC1 lead to a cystic phenotype of the Malpigian tubules in Drosophila melanogaster and are associated with PKD in vertebrates.

  • Environmental changes that are associated with renal pathophysiology, such as hypo-osmolality or hypoxia, can modulate RNA–protein interactions.

  • RNA–protein interactions can be inhibited and are potential therapeutic targets for various kidney diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: mRNA–RBP interactions in cellular biology.
Fig. 2: ncRNA–RBP interactions in cellular biology.
Fig. 3: Human antigen R in kidney disease.
Fig. 4: RNA-binding proteins in kidney disease.

Similar content being viewed by others

References

  1. Kapeli, K., Martinez, F. J. & Yeo, G. W. Genetic mutations in RNA-binding proteins and their roles in ALS. Hum. Genet. 136, 1193–1214 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lukong, K. E., Chang, K. W., Khandjian, E. W. & Richard, S. RNA-binding proteins in human genetic disease. Trends Genet. 24, 416–425 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Gebauer, F., Schwarzl, T., Valcárcel, J. & Hentze, M. W. RNA-binding proteins in human genetic disease. Nat. Rev. Genet. 22, 185–198 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Gerstberger, S., Hafner, M. & Tuschl, T. A census of human RNA-binding proteins. Nat. Rev. Genet. 15, 829–845 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Singh, G., Pratt, G., Yeo, G. W. & Moore, M. J. The clothes make the mRNA: past and present trends in mRNP fashion. Annu. Rev. Biochem. 84, 325–354 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ho, J. J. D. et al. A network of RNA-binding proteins controls translation efficiency to activate anaerobic metabolism. Nat. Commun. 11, 1–16 (2020).

    Article  Google Scholar 

  7. Dassi, E. Handshakes and fights: the regulatory interplay of RNA-binding proteins. Front. Mol. Biosci. 4, 67 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vázquez-Chantada, M. et al. HuR/Methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis. Gastroenterology 138, 1943–1953 (2010).

    Article  PubMed  Google Scholar 

  9. Sun, S. et al. Autotaxin expression is regulated at the post-transcriptional level by the RNA-binding proteins HuR and AUF1. J. Biol. Chem. 291, 25823–25836 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Poganik, J. R. et al. Post-transcriptional regulation of Nrf2-mRNA by the mRNA-binding proteins HuR and AUF1. FASEB J. 33, 14636–14652 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang, J., Hjelmeland, A. B., Nabors, L. B. & King, P. H. Anti-cancer effects of the HuR inhibitor, MS-444, in malignant glioma cells. Cancer Biol. Ther. 20, 979–988 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. García-Mauriño, S. M. et al. RNA binding protein regulation and cross-talk in the control of AU-rich mRNA fate. Front. Mol. Biosci. 4, 71 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Baltz, A. G. et al. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell 46, 674–690 (2012). Landmark study implementing RNA-interactome capture based on 4-SU labelling and UVA crosslinking.

    Article  CAS  PubMed  Google Scholar 

  14. Castello, A. et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012). Landmark study implementing RNA-interactome capture based on UVC crosslinking.

    Article  CAS  PubMed  Google Scholar 

  15. Conrad, T. et al. Serial interactome capture of the human cell nucleus. Nat. Commun. 7, 11212 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Licatalosi, D. D. et al. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464–469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hafner, M. et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129–141 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. König, J. et al. ICLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat. Struct. Mol. Biol. 17, 909–915 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Van Nostrand, E. L. et al. Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat. Methods 13, 508–514 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sharma, D. et al. The kinetic landscape of an RNA-binding protein in cells. Nature 591, 152–156 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Caudron-Herger, M., Jansen, R. E., Wassmer, E. & Diederichs, S. RBP2GO: a comprehensive pan-species database on RNA-binding proteins, their interactions and functions. Nucleic Acids Res. 49, D425–D436 (2020). Minable tool for obtaining an insight into current knowledge on RBPs and their function.

    Article  PubMed Central  Google Scholar 

  22. Cléry, A., Blatter, M. & Allain, F. H. T. RNA recognition motifs: boring? Not quite. Curr. Opin. Struct. Biol. 18, 290–298 (2008).

    Article  PubMed  Google Scholar 

  23. Linder, P. & Jankowsky, E. From unwinding to clamping-the DEAD box RNA helicase family. Nat. Rev. Mol. Cell Biol. 12, 505–516 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Valverde, R., Edwards, L. & Regan, L. Structure and function of KH domains. FEBS J. 275, 2712–2726 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Beckmann, B. M. et al. The RNA-binding proteomes from yeast to man harbour conserved enigmRBPs. Nat. Commun. 6, 10127 (2015). Extensive analysis of RBPomes in several species showing the abundance of RBPs lacking a classical RNA-binding domain, so-called enigmRBPs.

    Article  CAS  PubMed  Google Scholar 

  26. Hentze, M. W., Castello, A., Schwarzl, T. & Preiss, T. A brave new world of RNA-binding proteins. Nat. Rev. Mol. Cell Biol. 19, 327–341 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Esmaillie, R. et al. Activation of hypoxia-inducible factor signaling modulates the RNA protein interactome in Caenorhabditis elegans. iScience 22, 466–476 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ignarski, M. et al. The RNA-protein interactome of differentiated kidney tubular epithelial cells. J. Am. Soc. Nephrol. 30, 564–576 (2019). The first global RBPome in cultured renal tubule cells and its modulation by hypoxia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hämmerle, M. et al. Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1). Hepatology 58, 1703–1712 (2013).

    Article  PubMed  Google Scholar 

  30. Wang, I. K. et al. The functional interplay of lncRNA EGOT and HuR regulates hypoxia-induced autophagy in renal tubular cells. J. Cell. Biochem. 121, 4522–4534 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. Fasolo, F. et al. The RNA-binding protein ILF3 binds to transposable element sequences in SINEUP lncRNAs. FASEB J. 33, 13572–13589 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wahl, M. C., Will, C. L. & Lührmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Wende, W., Friedhoff, P. & Sträßer, K. Mechanism and regulation of co-transcriptional mRNP assembly and nuclear mRNA export. Adv. Exp. Med. Biol. 1203, 1–31 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Rissland, O. S. The organization and regulation of mRNA–protein complexes. Wiley Interdiscip. Rev. RNA 8, e1369 (2017).

    Article  Google Scholar 

  35. Harvey, R. F. et al. Trans-acting translational regulatory RNA binding proteins. Wiley Interdiscip. Rev. RNA 9, e1465 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ivanov, P., Kedersha, N. & Anderson, P. Stress granules and processing bodies in translational control. Cold Spring Harb. Perspect. Biol. 11, a032813 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Darling, A. L., Liu, Y., Oldfield, C. J. & Uversky, V. N. Intrinsically disordered proteome of human membrane-less organelles. Proteomics 18, e1700193 (2018).

    Article  PubMed  Google Scholar 

  39. Wang, S., Kwon, S.-H., Su, Y., Dong, Z. & Norwood, C. Stress granules are formed in renal proximal tubular cells during metabolic stress and ischemic injury for cell survival. Am. J. Physiol. Renal Physiol. 317, 116–123 (2019).

    Article  Google Scholar 

  40. Estrada Mallarino, L. et al. Nephronophthisis gene products display RNA-binding properties and are recruited to stress granules. Sci. Rep. 10, 15954 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huang, B. & Zhang, R. Regulatory non-coding RNAs: revolutionizing the RNA world. Mol. Biol. Rep. 41, 3915–3923 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Matera, A. G. & Wang, Z. A day in the life of the spliceosome. Nat. Rev. Mol. Cell Biol. 15, 108–121 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Matera, A. G., Terns, R. M. & Terns, M. P. Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs. Nat. Rev. Mol. Cell Biol. 8, 209–220 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Schimmel, P. RNA processing and modifications: the emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis. Nat. Rev. Mol. Cell Biol. 19, 45–58 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Kaiser, R. W. J. et al. A protein-RNA interaction atlas of the ribosome biogenesis factor AATF. Sci. Rep. 9, 11071 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Klinge, S. & Woolford, J. L. Ribosome assembly coming into focus. Nat. Rev. Mol. Cell Biol. 20, 116–131 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Olina, A. V., Kulbachinskiy, A. V., Aravin, A. A. & Esyunina, D. M. Argonaute proteins and mechanisms of RNA interference in eukaryotes and prokaryotes. Biochemistry 83, 483–497 (2018).

    CAS  PubMed  Google Scholar 

  48. Ghildiyal, M. & Zamore, P. D. Small silencing RNAs: an expanding universe. Nat. Rev. Genet. 10, 94–108 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kristensen, L. S. et al. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 20, 675–691 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Yao, R. W., Wang, Y. & Chen, L. L. Cellular functions of long noncoding RNAs. Nat. Cell Biol. 21, 542–551 (2019).

    Article  CAS  PubMed  Google Scholar 

  51. Sun, X., Haider Ali, M. S. S. & Moran, M. The role of interactions of long non-coding RNAs and heterogeneous nuclear ribonucleoproteins in regulating cellular functions. Biochem. J. 474, 2925–2935 (2017).

    Article  CAS  PubMed  Google Scholar 

  52. Kazimierczyk, M., Kasprowicz, M. K., Kasprzyk, M. E. & Wrzesinski, J. Human long noncoding RNA interactome: detection, characterization and function. Int. J. Mol. Sci. 21, 1027 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  53. Copsey, A. C. et al. The helicase, DDX3X, interacts with poly(A)-binding protein 1 (PABP1) and caprin-1 at the leading edge of migrating fibroblasts and is required for efficient cell spreading. Biochem. J. 474, 3109–3120 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Johnsen, M. et al. The integrated RNA landscape of renal preconditioning against ischemia-reperfusion injury. J. Am. Soc. Nephrol. 31, 716–730 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Colombrita, C., Silani, V. & Ratti, A. ELAV proteins along evolution: back to the nucleus? Mol. Cell. Neurosci. 56, 447–455 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. De Toeuf, B. et al. ARE-mediated decay controls gene expression and cellular metabolism upon oxygen variations. Sci. Rep. 8, 5211 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Brennan, C. M. & Steitz, J. A. HuR and mRNA stability. Cell. Mol. Life Sci. 58, 266–277 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Hinman, M. N. & Lou, H. Diverse molecular functions of Hu proteins. Cell. Mol. Life Sci. 65, 3168–3181 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jonas, K., Calin, G. A. & Pichler, M. RNA-binding proteins as important regulators of long non-coding RNAs in cancer. Int. J. Mol. Sci. 21, 2969 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  60. Abdelmohsen, K. et al. Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biol. 14, 361–369 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Li, X.-X. et al. Interaction between HuR and circPABPN1 modulates autophagy in the intestinal epithelium by altering ATG16L1 translation. Mol. Cell. Biol. 40, e00492–19 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Grammatikakis, I., Abdelmohsen, K. & Gorospe, M. Posttranslational control of HuR function. RNA 8, 10.1002/wrna.1372 (2017).

  63. Jeyaraj, S., Dakhlallah, D., Mill, S. R. & Lee, B. S. HuR stabilizes vacuolar H+-translocating ATPase mRNA during cellular energy depletion. J. Biol. Chem. 280, 37957–37964 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Jeyaraj, S. C., Dakhlallah, D., Hill, S. R. & Lee, B. S. Expression and distribution of HuR during ATP depletion and recovery in proximal tubule cells. Am. J. Physiol. Renal Physiol. 291, F1255–F1263 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Jeyaraj, S. C., Singh, M., Ayupova, D. A., Govindaraju, S. & Lee, B. S. Transcriptional control of human antigen R by bone morphogenetic protein. J. Biol. Chem. 285, 4432–4440 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Govindaraju, S. & Lee, B. S. Krüppel-like factor 8 is a stress-responsive transcription factor that regulates expression of HuR. Cell. Physiol. Biochem. 34, 519–532 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Ayupova, D. A., Singh, M., Leonard, E. C., Basile, D. P. & Lee, B. S. Expression of the RNA-stabilizing protein HuR in ischemia-reperfusion injury of rat kidney. Am. J. Physiol. Renal Physiol. 297, F95–F105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Singh, M., Martinez, A. R., Govindaraju, S. & Lee, B. S. HuR inhibits apoptosis by amplifying Akt signaling through a positive feedback loop. J. Cell. Physiol. 228, 182–189 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jiang, M., Liu, K., Luo, J. & Dong, Z. Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury. Am. J. Pathol. 176, 1181–1192 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jiang, M. et al. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 82, 1271–1283 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Palanisamy, K. et al. RNA-binding protein, human antigen R regulates hypoxia-induced autophagy by targeting ATG7/ATG16L1 expressions and autophagosome formation. J. Cell. Physiol. 234, 7448–7458 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Bolisetty, S., Zarjou, A. & Agarwal, A. Heme oxygenase 1 as a therapeutic target in acute kidney injury. Am. J. Kidney Dis. 69, 531–545 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li, S. et al. Hyperhomocysteinemia accelerates acute kidney injury to chronic kidney disease progression by downregulating heme oxygenase-1 expression. Antioxid. Redox Signal. 30, 1635–1650 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Long, Y. & Nie, J. Homocysteine in renal injury. Kidney Dis. 2, 80–87 (2016).

    Article  Google Scholar 

  75. Nishiyama, H. et al. A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth. J. Cell Biol. 137, 898–908 (1997).

    Article  Google Scholar 

  76. Zhu, X., Bührer, C. & Wellmann, S. Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond the cold. Cell. Mol. Life Sci. 73, 3839–3859 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Peng, Y. et al. Maternal cold inducible RNA binding protein is required for embryonic kidney formation in Xenopus laevis. FEBS Lett. 482, 37–43 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Cen, C. et al. Deficiency of cold-inducible ribonucleic acid-binding protein reduces renal injury after ischemia-reperfusion. Surgery 160, 473–483 (2016).

    Article  PubMed  Google Scholar 

  79. McGinn, J. et al. The protective effect of a short peptide derived from cold-inducible RNA-binding protein in renal ischemia-reperfusion injury. Shock 49, 269–276 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhang, F., Brenner, M., Yang, W. L. & Wang, P. A cold-inducible RNA-binding protein (CIRP)-derived peptide attenuates inflammation and organ injury in septic mice. Sci. Rep. 8, 3052 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Xia, Z. et al. Mild hypothermia protects renal function in ischemia-reperfusion kidney: an experimental study in mice. Transplant. Proc. 50, 3816–3821 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Yu, L., Gu, T., Liu, Y., Jiang, X. & Shi, E. Cold-inducible ribonucleic acid-binding protein attenuates acute kidney injuries after deep hypothermic circulatory arrest in rats. Interact. Cardiovasc. Thorac. Surg. 26, 124–130 (2018).

    Article  PubMed  Google Scholar 

  83. Zuo, Z. et al. Mechanisms and functions of mitophagy and potential roles in renal disease. Front. Physiol. 11, 935 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Perry, H. M. et al. Dynamin-related protein 1 deficiency promotes recovery from AKI. J. Am. Soc. Nephrol. 29, 194–206 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Wang, J. et al. Pum2-Mff axis fine-tunes mitochondrial quality control in acute ischemic kidney injury. Cell Biol. Toxicol. 36, 365–378 (2020).

    Article  CAS  PubMed  Google Scholar 

  86. D’Amico, D. et al. The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Mol. Cell 73, 775–787.e10 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Goodarzi, H. et al. Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement. Cell 161, 790–802 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wu, S. L. et al. Genome-wide analysis of YB-1-RNA interactions reveals a novel role of YB-1 in miRNA processing in glioblastoma multiforme. Nucleic Acids Res. 43, 8516–8528 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mordovkina, D. et al. Y-box binding proteins in mRNP assembly, translation, and stability control. Biomolecules 10, 591 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  90. Yong, W. et al. The role of YB1 in renal cell carcinoma cell adhesion. Int. J. Med. Sci. 15, 1304–1311 (2018).

    Article  Google Scholar 

  91. Yong, W. et al. The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1-SPP1-NF-κB signaling axis. J. Exp. Clin. Cancer Res 38, 386 (2019).

    Article  Google Scholar 

  92. Yong, W. et al. CD4+ T cells promote renal cell carcinoma proliferation via modulating YBX1. Exp. Cell Res. 363, 95–101 (2018).

    Article  Google Scholar 

  93. Dong, W. et al. Activated protein C ameliorates renal ischemia-reperfusion injury by restricting Y-box binding protein-1 ubiquitination. J. Am. Soc. Nephrol. 26, 2789–2799 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hanssen, L. et al. Y-box binding protein-1 mediates profibrotic effects of calcineurin inhibitors in the kidney. J. Immunol. 187, 298–308 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Gibbert, L. et al. YB-1 increases glomerular, but decreases interstitial fibrosis in CNI-induced nephropathy. Clin. Immunol. 194, 67–74 (2018).

    Article  CAS  PubMed  Google Scholar 

  96. Raffetseder, U. et al. Differential regulation of chemokine CCL5 expression in monocytes/macrophages and renal cells by Y-box protein-1. Kidney Int. 75, 185–196 (2009). This work provides important additional insight into the function of YBX1 in renal disease.

    Article  CAS  PubMed  Google Scholar 

  97. Hanssen, L. et al. YB-1 is an early and central mediator of bacterial and sterile inflammation in vivo. J. Immunol. 191, 2604–2613 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Bhreathnach, U. et al. Profibrotic IHG-1 complexes with renal disease associated HSPA5 and TRAP1 in mitochondria. Biochim. Biophys. Acta 1863, 896–906 (2017).

    Article  CAS  Google Scholar 

  99. Wang, J. et al. Therapeutic nuclear shuttling of YB-1 reduces renal damage and fibrosis. Kidney Int. 90, 1226–1237 (2016). Important work as an example of how RBP function can be modulated to tackle renal disease.

    Article  CAS  PubMed  Google Scholar 

  100. Kato, M. et al. Post-transcriptional up-regulation of Tsc-22 by Ybx1, a target of miR-216a, mediates TGF-β-induced collagen expression in kidney cells. J. Biol. Chem. 285, 3404–3415 (2010).

    Article  Google Scholar 

  101. Van Roeyen, C. R. C. et al. Y-box protein 1 mediates PDGF-B effects in mesangioproliferative glomerular disease. J. Am. Soc. Nephrol. 16, 2985–2996 (2005). Central study regarding the RBP YBX1 in MPGN and its role in PDGFB signalling.

    Article  PubMed  Google Scholar 

  102. Webster, A. C., Nagler, E. V., Morton, R. L. & Masson, P. Chronic kidney disease. Lancet 389, 1238–1252 (2017).

    Article  PubMed  Google Scholar 

  103. Moranne, O. et al. Timing of onset of CKD-related metabolic complications. J. Am. Soc. Nephrol. 20, 164–171 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Bürki, R. et al. Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease. Nephrol. Dial. Transplant. 30, 770–781 (2015).

    Article  PubMed  Google Scholar 

  105. Mufti, J. et al. Role of AUF1 and HuR in the pH-responsive stabilization of phosphoenolpyruvate carboxykinase mRNA in LLC-PK 1-F+ cells. Am. J. Physiol. Renal Physiol. 301, F1066–F1077 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gummadi, L., Taylor, L. & Curthoys, N. P. Concurrent binding and modifications of AUF1 and HuR mediate the pH-responsive stabilization of phosphoenolpyruvate carboxykinase mRNA in kidney cells. Am. J. Physiol. Renal Physiol. 303, F1545–F1554 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Muntner, P. et al. Hypertension awareness, treatment, and control in adults with CKD: results from the chronic renal insufficiency cohort (CRIC) study. Am. J. Kidney Dis. 55, 441–451 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Townsend, R. R. & Taler, S. J. Management of hypertension in chronic kidney disease. Nat. Rev. Nephrol. 11, 555–563 (2015).

    Article  PubMed  Google Scholar 

  109. Quinkler, M. et al. Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria. Circulation 112, 1435–1443 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Alexandrou, M. E. et al. Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease: a systematic review and meta-analysis of randomized controlled trials. J. Hypertens. 37, 2307–2324 (2019).

    Article  CAS  PubMed  Google Scholar 

  111. Viengchareun, S. et al. Osmotic stress regulates mineralocorticoid receptor expression in a novel aldosterone-sensitive cortical collecting duct cell line. Mol. Endocrinol. 23, 1948–1962 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lema, I. et al. RNA-binding protein HuR enhances mineralocorticoid signaling in renal KC3AC1 cells under hypotonicity. Cell. Mol. Life Sci. 74, 4587–4597 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Lema, I. et al. HuR-dependent editing of a new mineralocorticoid receptor splice variant reveals an osmoregulatory loop for sodium homeostasis. Sci. Rep. 7, 4835 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Viengchareun, S. et al. Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11b-mediated post-transcriptional control. J. Am. Soc. Nephrol. 25, 2213–2221 (2014). Important work regarding the role of an RBP in renal mineralocorticoid receptor signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Igarashi, P. & Somlo, S. Polycystic kidney disease. J. Am. Soc. Nephrol. 18, 1371–1373 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Saffman, E. E. et al. Premature translation of oskar in oocytes lacking the RNA-binding protein bicaudal-C. Mol. Cell. Biol. 18, 4855–4862 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gamberi, C. & Lasko, P. The Bic-C family of developmental translational regulators. Comp. Funct. Genomics 2012, 141386 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zhang, Y. et al. Bicaudal-C spatially controls translation of vertebrate maternal mRNAs. RNA 19, 1575–1582 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhang, Y., Park, S., Blaser, S. & Sheets, M. D. Determinants of RNA binding and translational repression by the Bicaudal-C regulatory protein. J. Biol. Chem. 289, 7497–7504 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dowdle, M. E. et al. A single KH domain in Bicaudal-C links mRNA binding and translational repression functions to maternal development. Development 146, dev172486 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lian, P. et al. Loss of polycystin-1 inhibits Bicc1 expression during mouse development. PLoS One 9, e88816 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Mohieldin, A. M. et al. Protein composition and movements of membrane swellings associated with primary cilia. Cell. Mol. Life Sci. 72, 2415–2429 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Cogswell, C. et al. Positional cloning of jcpk/bpk locus of the mouse. Mamm. Genome 14, 242–249 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Bouvrette, D. J., Price, S. J. & Bryda, E. C. K homology domains of the mouse polycystic kidney disease-related protein, Bicaudal-C (Bicc1), mediate RNA binding in vitro. Nephron Exp. Nephrol. 108, e27–e34 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Tran, U., Pickney, L. M., Özpolat, B. D. & Wessely, O. Xenopus Bicaudal-C is required for the differentiation of the amphibian pronephros. Dev. Biol. 307, 152–164 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bouvrette, D. J., Sittaramane, V., Heidel, J. R., Chandrasekhar, A. & Bryda, E. C. Knockdown of bicaudal C in zebrafish (Danio rerio) causes cystic kidneys: a nonmammalian model of polycystic kidney disease. Comp. Med. 60, 96–106 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Stagner, E. E., Bouvrette, D. J., Cheng, J. & Bryda, E. C. The polycystic kidney disease-related proteins Bicc1 and SamCystin interact. Biochem. Biophys. Res. Commun. 383, 16–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Bakey, Z. et al. The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes. Kidney Int. 88, 299–310 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Brown, J. H. et al. Missense mutation in sterile α motif of novel protein SamCystin is associated with polycystic kidney disease in (cy/+) rat. J. Am. Soc. Nephrol. 16, 3517–3526 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Rothé, B. et al. Crystal structure of Bicc1 SAM polymer and mapping of interactions between the ciliopathy-associated proteins Bicc1, ANKS3, and ANKS6. Structure 26, 209–224 (2018).

    Article  PubMed  Google Scholar 

  131. Fu, Y. et al. Loss of Bicc1 impairs tubulomorphogenesis of cultured IMCD cells by disrupting E-cadherin-based cell-cell adhesion. Eur. J. Cell Biol. 89, 428–436 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Maisonneuve, C. et al. Bicaudal C, a novel regulator of Dvl signaling abutting RNA-processing bodies, controls cilia orientation and leftward flow. Development 136, 3019–3030 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Kraus, M. R. C. et al. Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia. Hum. Mutat. 33, 86–90 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Piazzon, N., Maisonneuve, C., Guilleret, I., Rotman, S. & Constam, D. B. Bicc1 links the regulation of cAMP signaling in polycystic kidneys to microRNA-induced gene silencing. J. Mol. Cell Biol. 4, 398–408 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Tran, U. et al. The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity. Development 137, 1107–1116 (2010). This work not only implicates the RBP bicaudal C in PKD but also shows its molecular function by antagonizing an miRNA known to play a role in cystogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lemaire, L. A. et al. Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis. Development 142, 858–870 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Leal-Esteban, L. C., Rothé, B., Fortier, S., Isenschmid, M. & Constam, D. B. Role of bicaudal C1 in renal gluconeogenesis and its novel interaction with the CTLH complex. PLoS Genet. 14, e1007487 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Gamberi, C., Hipfner, D. R., Trudel, M. & Lubell, W. D. Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila. PLoS Genet. 13, e1006694 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Debaize, L. & Troadec, M. B. The master regulator FUBP1: its emerging role in normal cell function and malignant development. Cell. Mol. Life Sci. 76, 259–281 (2019).

    Article  CAS  PubMed  Google Scholar 

  140. Zheng, W. et al. Far upstream element-binding protein 1 binds the 39 untranslated region of PKD2 and suppresses its translation. J. Am. Soc. Nephrol. 27, 2645–2657 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Liu, Y. Cellular and molecular mechanisms of renal fibrosis. Nat. Rev. Nephrol. 10, 493–503 (2011).

    Google Scholar 

  142. Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. Inflammatory processes in renal fibrosis. Nat. Rev. Nephrol. 10, 493–503 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. Bülow, R. D. & Boor, P. Extracellular matrix in kidney fibrosis: more than just a scaffold. J. Histochem. Cytochem. 67, 643–661 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Gregorini, M. et al. Mesenchymal stromal cells prevent renal fibrosis in a rat model of unilateral ureteral obstruction by suppressing the renin-angiotensin system via HuR. PLoS One 11, e0148542 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Chen, X. et al. The potential role of retinoic acid receptor α on glomerulosclerosis in rats and podocytes injury is associated with the induction of MMP2 and MMP9. Acta Biochim. Biophys. Sin. 49, 669–679 (2017).

    Article  CAS  PubMed  Google Scholar 

  146. Tsai, J. P. et al. Increased expression of intranuclear matrix metalloproteinase 9 in atrophic renal tubules is associated with renal fibrosis. PLoS One 7, e48164 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wang, X. et al. Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy. Am. J. Physiol. Renal Physiol. 299, F973–F982 (2010).

    Article  CAS  PubMed  Google Scholar 

  148. Yokoo, T. & Kitamura, M. Dual regulation of IL-1β-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kappaB and AP-1. Am. J. Physiol. 270, F123–F130 (1996).

    CAS  PubMed  Google Scholar 

  149. Huwiler, A. et al. ATP potentiates interleukin-1β-induced MMP-9 expression in mesangial cells via recruitment of the ELAV Protein HuR. J. Biol. Chem. 278, 51758–51769 (2003). This study provides first evidence of the role of the RBP HuR in mesangial cells.

    Article  CAS  PubMed  Google Scholar 

  150. Akool, E.-S. et al. Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. Mol. Cell. Biol. 23, 4901–4916 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  151. Cok, S. J., Acton, S. J. & Morrison, A. R. The proximal region of the 3′-untranslated region of cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR, TIA-1, TIAR, and the heterogeneous nuclear ribonucleoprotein U. J. Biol. Chem. 278, 36157–36162 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Doller, A. et al. Protein kinase Cα-dependent phosphorylation of the mRNA-stabilizing factor HuR: Implications for posttranscriptional regulation of cyclooxygenase-2. Mol. Biol. Cell 28, 2608–2625 (2007).

    Article  Google Scholar 

  153. Doller, A. et al. Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cδ elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. Mol. Cell. Biol. 28, 2608–2625 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Doller, A. et al. Angiotensin II induces renal plasminogen activator inhibitor-1 and cyclooxygenase-2 expression post-transcriptionally via activation of the mRNA-stabilizing factor human-antigen R. Am. J. Pathol. 174, 1252–1263 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kitching, A. R. et al. Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic glomerulonephritis. J. Am. Soc. Nephrol. 14, 1487–1495 (2003).

    Article  PubMed  Google Scholar 

  156. Kurogi, Y. Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease. Med. Res. Rev. 23, 15–31 (2003).

    Article  CAS  PubMed  Google Scholar 

  157. Lang, S., Hartner, A., Sterzel, R. B. & Schöcklmann, H. O. Requirement of cyclin D1 in mesangial cell mitogenesis. J. Am. Soc. Nephrol. 11, 1398–1408 (2000).

    Article  CAS  PubMed  Google Scholar 

  158. Doller, A., Schlepckow, K., Schwalbe, H., Pfeilschifter, J. & Eberhardt, W. Tandem phosphorylation of serines 221 and 318 by protein kinase Cδ coordinates mRNA binding and nucleocytoplasmic shuttling of HuR. Mol. Cell. Biol. 30, 1397–1410 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Che, Y. et al. AngiotensinII induces HuR shuttling by post-transcriptional regulated cyclinD1 in human mesangial cells. Mol. Biol. Rep. 41, 1141–1150 (2014).

    Article  CAS  PubMed  Google Scholar 

  160. Lellek, H. et al. Purification and molecular cloning of a novel essential component of the apolipoprotein B mRNA editing enzyme-complex. J. Biol. Chem. 275, 19848–19856 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Snyder, E. M. et al. APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo. RNA 23, 457–465 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Huang, L. et al. Apobec-1 complementation factor (A1CF) inhibits epithelial-mesenchymal transition and migration of normal rat kidney proximal tubular epithelial cells. Int. J. Mol. Sci. 17, 197 (2016).

    Article  PubMed Central  Google Scholar 

  163. Kumar, R. Pin1 regulates parathyroid hormone mRNA stability. J. Clin. Invest. 119, 2887–2891 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Yan, J. et al. AUF1 modulates TGF-β signal in renal tubular epithelial cells via post-transcriptional regulation of Nedd4L expression. Biochim. Biophys. Acta Mol. Cell Res. 1865, 48–56 (2018).

    Article  CAS  PubMed  Google Scholar 

  165. Gao, S. et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling. Mol. Cell 36, 457–468 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Stradiot, L., Mannaerts, I. & Van Grunsven, L. A. P311, friend, or foe of tissue fibrosis? Front. Pharmacol. 9, 1151 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Yue, M. M. et al. Novel RNA-binding protein P311 binds Eukaryotic translation initiation factor 3 subunit B (eIF3b) to promote translation of transforming growth factor β1-3 (TGF-β1-3). J. Biol. Chem. 289, 33971–33983 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wang, F. et al. Expression of P311, a transforming growth factor beta latency-associated protein-binding protein, in human kidneys with IgA nephropathy. Int. Urol. Nephrol. 42, 811–819 (2010).

    Article  CAS  PubMed  Google Scholar 

  169. Zhang, Y. et al. Role of P311 in interleukin-1α-induced epithelial to myofibroblast transition in kidney tubular epithelial cells. Ren. Fail. 37, 1384–1389 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Yao, Z. et al. P311 promotes renal fibrosis via TGFβ1/Smad signaling. Sci. Rep. 5, 17032 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wei, Z. et al. Molecular mechanism of mesenchyme homeobox 1 in transforming growth factor β1–induced P311 gene transcription in fibrosis. Front. Mol. Biosci. 7, 59 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Qi, F., Cai, P., Liu, X., Peng, M. & Si, G. Adenovirus-mediated P311 inhibits TGF-β1-induced epithelial–mesenchymal transition in NRK-52E cells via TGF-β1-Smad-ILK pathway. Biosci. Trends 9, 299–306 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Qi, F. H., Cai, P. P., Liu, X. & Si, G. M. Adenovirus-mediated P311 ameliorates renal fibrosis through inhibition of epithelial-mesenchymal transition via TGF-β1-Smad-ILK pathway in unilateral ureteral obstruction rats. Int. J. Mol. Med. 41, 3015–3023 (2018).

    CAS  PubMed  Google Scholar 

  174. Wagener, N. et al. Expression of inhibitor of apoptosis protein Livin in renal cell carcinoma and non-tumorous adult kidney. Br. J. Cancer 97, 1271–1276 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Zhou, J. & Jiang, H. Livin is involved in TGF-β1-induced renal tubular epithelial-mesenchymal transition through lncRNA-ATB. Ann. Transl. Med. 7, 463 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. das Chagas, P. F., Baroni, M., Brassesco, M. S. & Tone, L. G. Interplay between the RNA binding-protein Musashi and developmental signaling pathways. J. Gene Med. 22, e3136 (2020).

    Article  PubMed  Google Scholar 

  177. Jadhav, S. et al. RNA-binding protein Musashi homologue 1 regulates kidney fibrosis by translational inhibition of p21 and Numb mRNA. J. Biol. Chem. 291, 14085–14094 (2016). Important work showing how an RBP (MSI1) impacts on renal fibrogenesis by binding to its target mRNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Ume, A. C., Wenegieme, T.-Y. & Williams, C. R. Calcineurin inhibitors: a double-edged sword. Am. J. Physiol. Renal Physiol. 320, F336–F341 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Wang, J. et al. YB-1 orchestrates onset and resolution of renal inflammation via IL10 gene regulation. J. Cell. Mol. Med. 21, 3494–3505 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Bernhardt, A. et al. Inflammatory cell infiltration and resolution of kidney inflammation is orchestrated by the cold-shock protein Y-box binding protein-1. Kidney Int. 92, 1157–1177 (2017).

    Article  CAS  PubMed  Google Scholar 

  181. Ewert, L. et al. Cold shock Y-box binding protein-1 acetylation status in monocytes is associated with systemic inflammation and vascular damage. Atherosclerosis 278, 156–165 (2018).

    Article  CAS  PubMed  Google Scholar 

  182. Brandt, S. et al. Altered monocytic phenotypes are linked with systemic inflammation and may be linked to mortality in dialysis patients. Sci. Rep. 9, 19103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hermert, D. et al. The nucleic acid binding protein YB-1-controlled expression of CXCL-1 modulates kidney damage in liver fibrosis. Kidney Int. 97, 741–752 (2020).

    Article  CAS  PubMed  Google Scholar 

  184. Thomas, M. C. et al. Diabetic kidney disease. Nat. Rev. Dis. Prim. 1, 15018 (2015).

    Article  PubMed  Google Scholar 

  185. Navarro-González, J. F., Mora-Fernández, C., De Fuentes, M. M. & García-Pérez, J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat. Rev. Nephrol. 7, 327–340 (2011).

    Article  PubMed  Google Scholar 

  186. Yu, C. et al. Human antigen R mediated post-transcriptional regulation of epithelial-mesenchymal transition related genes in diabetic nephropathy. J. Diabetes 7, 562–572 (2015).

    Article  CAS  PubMed  Google Scholar 

  187. Li, X. et al. Long noncoding RNA MALAT1 regulates renal tubular epithelial pyroptosis by modulated miR-23c targeting of ELAVL1 in diabetic nephropathy. Exp. Cell Res. 350, 327–335 (2017).

    Article  CAS  PubMed  Google Scholar 

  188. Shahzad, K. et al. Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 87, 74–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  189. Du, P. et al. NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int. 84, 265–276 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Shang, J. et al. Identification of NOD2 as a novel target of RNA-binding protein HuR: evidence from NADPH oxidase-mediated HuR signaling in diabetic nephropathy. Free Radic. Biol. Med. 79, 217–227 (2015).

    Article  CAS  PubMed  Google Scholar 

  191. Shi, Q. et al. Interplay between RNA-binding protein HuR and Nox4 as a novel therapeutic target in diabetic kidney disease. Mol. Metab. 36, 100968 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Guo, J. et al. RNA-binding proteins tristetraprolin and human antigen R are novel modulators of podocyte injury in diabetic kidney disease. Cell Death Dis. 11, 413 (2020). This study shows the interactions between two RBPs regarding podocyte injury in diabetic kidney disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Brooks, S. A. & Blackshear, P. J. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim. Biophys. Acta 1829, 666–679 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Taylor, G. A. et al. A pathogenetic role for TNFα in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4, 445–454 (1996).

    Article  CAS  PubMed  Google Scholar 

  195. Liu, F. et al. The expression of tristetraprolin and its relationship with urinary proteins in patients with diabetic nephropathy. PLoS One 10, e0141471 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Guo, J. et al. MiRNA-29c regulates the expression of inflammatory cytokines in diabetic nephropathy by targeting tristetraprolin. Sci. Rep. 7, 2314 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Zhang, Q., Wu, G., Guo, S., Liu, Y. & Liu, Z. Effects of tristetraprolin on doxorubicin (adriamycin)-induced experimental kidney injury through inhibiting IL-13/STAT6 signal pathway. Am. J. Transl. Res. 12, 1203–1221 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Christiansen, J., Kolte, A. M., Hansen, T. V. O. & Nielsen, F. C. IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes. J. Mol. Endocrinol. 43, 187–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  199. Gu, T. et al. IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy. J. Diabetes Complications 26, 393–398 (2012).

    Article  PubMed  Google Scholar 

  200. Schaeffer, V., Hansen, K. M., Morris, D. R., LeBoeuf, R. C. & Abrass, C. K. RNA-binding protein IGF2BP2/IMP2 is required for laminin-β2 mRNA translation and is modulated by glucose concentration. Am. J. Physiol. Renal Physiol. 303, F75–F82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Jing, F., Zhao, J., Jing, X. & Lei, G. Long noncoding RNA Airn protects podocytes from diabetic nephropathy lesions via binding to Igf2bp2 and facilitating translation of Igf2 and Lamb2. Cell Biol. Int. 44, 1860–1869 (2020).

    Article  CAS  PubMed  Google Scholar 

  202. Jiang, X. et al. Metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR-130a-3p/STAT3 pathway. Oxid. Med. Cell. Longev. 2020, 8708236 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Wiley, C. D. Role of senescent renal cells in pathophysiology of diabetic kidney disease. Curr. Diabetes Rep. 20, 1–7 (2020).

    Article  Google Scholar 

  204. Du, Y. et al. Butyrate alleviates diabetic kidney disease by mediating the miR-7a-5p/P311/TGF-β1 pathway. FASEB J. 34, 10462–10475 (2020).

    Article  CAS  PubMed  Google Scholar 

  205. Christodoulou-Vafeiadou, E. et al. Divergent innate and epithelial functions of the RNA-binding protein HuR in intestinal inflammation. Front. Immunol. 9, 2732 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Nyati, K. K., Zaman, M. M.-U., Sharma, P. & Kishimoto, T. Arid5a, an RNA-binding protein in immune regulation: RNA stability, inflammation, and autoimmunity. Trends Immunol. 41, 255–268 (2020).

    Article  CAS  PubMed  Google Scholar 

  207. Chelsey, J. L. et al. Reduction of the RNA binding protein TIA1 exacerbates neuroinflammation in tauopathy. Front. Neurosci. 14, 285 (2020).

    Article  Google Scholar 

  208. Emine, S., Suna Özbaş, T. & Jülide, A. Inhibition of glomerular mesangial cell proliferation by siPDGF-B- and siPDGFR-β-containing chitosan nanoplexes. AAPS PharmSciTech 18, 1031–1042 (2017).

    Article  Google Scholar 

  209. Jürgen, F., Frank, E. & Charles, E. A. A new look at platelet-derived growth factor in renal disease. J. Am. Soc. Nephrol. 19, 12–23 (2008).

    Article  Google Scholar 

  210. Raffetseder, U. et al. Extracellular YB-1 blockade in experimental nephritis upregulates Notch-3 receptor expression and signaling. Nephron Exp. Nephrol. 118, e100–e108 (2011).

    Article  CAS  PubMed  Google Scholar 

  211. Zhu, X. et al. Protein phosphatase 2A modulates podocyte maturation and glomerular functional integrity in mice. Cell Commun. Signal. 17, 91 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Liu, S. et al. Inhibition of RNA-binding protein HuR reduces glomerulosclerosis in experimental nephritis. Clin. Sci. 134, 1433–1448 (2020).

    Article  CAS  Google Scholar 

  213. Das, S. & Krainer, A. R. Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer. Mol. Cancer Res. 12, 1195–1204 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Kono, M. et al. Decreased expression of serine/arginine-rich splicing factor 1 in T cells from patients with active systemic lupus erythematosus accounts for reduced expression of RasGRP1 and DNA methyltransferase 1. Arthritis Rheumatol. 70, 2046–2056 (2018).

    Article  CAS  PubMed  Google Scholar 

  215. Katsuyama, T., Li, H., Comte, D., Tsokos, G. C. & Moulton, V. R. Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity. J. Clin. Invest. 129, 5411–5423 (2019). Important work showing the impact of the SLE-associated RBP SRSF1 in nephrotoxic serum nephritis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Katsuyama, T., Li, H., Krishfield, S. M., Kyttaris, V. C. & Moulton, V. R. Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis. Rheumatology 60, 420–429 (2020).

    Article  PubMed Central  Google Scholar 

  217. Wu, P. Inhibition of RNA-binding proteins with small molecules. Nat. Rev. Chem. 4, 441–458 (2020).

    Article  CAS  Google Scholar 

  218. Lieberman, J. Tapping the RNA world for therapeutics. Nat. Struct. Mol. Biol. 25, 357–364 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Mohibi, S., Chen, X. & Zhang, J. Cancer the ‘RBP’ eutics–RNA-binding proteins as therapeutic targets for cancer. Pharmacol. Ther. 203, 107390 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Sanna, M. D., Quattrone, A. & Galeotti, N. Silencing of the RNA-binding protein HuR attenuates hyperalgesia and motor disability in experimental autoimmune encephalomyelitis. Neuropharmacology 123, 116–125 (2017).

    Article  CAS  PubMed  Google Scholar 

  221. Fox, R. G. et al. Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534, 407–411 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Amreddy, N. et al. Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment. Nanomed. Nanotechnol. Biol. Med. 14, 373–384 (2018).

    Article  CAS  Google Scholar 

  223. Huang, Y. H. et al. Delivery of therapeutics targeting the mRNA binding protein HuR Using 3DNA nanocarriers suppresses ovarian tumor growth. Cancer Res. 76, 1549–1559 (2016).

    Article  CAS  PubMed  Google Scholar 

  224. Chen, H. et al. Inhibition of RNA-binding protein Musashi-1 suppresses malignant properties and reverses paclitaxel resistance in ovarian carcinoma. J. Cancer 10, 1580–1592 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Baranello, G. et al. Risdiplam in type 1 spinal muscular atrophy. N. Engl. J. Med. 384, 915–923 (2021).

    Article  CAS  PubMed  Google Scholar 

  226. Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  227. Balwani, M. et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N. Engl. J. Med. 382, 2289–2301 (2020).

    Article  CAS  PubMed  Google Scholar 

  228. Agency, E. M. First treatment for rare condition primary hyperoxaluria type 1. https://www.ema.europa.eu/en/news/first-treatment-rare-condition-primary-hyperoxaluria-type-1 (2020).

  229. Dammes, N. & Peer, D. Paving the road for RNA therapeutics. Trends Pharmacol. Sci. 41, 755–775 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Meisner, N. C. et al. Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR. Nat. Chem. Biol. 3, 508–515 (2007).

    Article  CAS  PubMed  Google Scholar 

  231. Blanco, F. F. et al. Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis. Oncotarget 7, 74043–74058 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Lang, M. et al. HuR small-molecule inhibitor elicits differential effects in adenomatosis polyposis and colorectal carcinogenesis. Cancer Res. 77, 2424–2438 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Muralidharan, R. et al. HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells. Sci. Rep. 7, 9694 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Allegri, L. et al. The HuR CMLD-2 inhibitor exhibits antitumor effects via MAD2 downregulation in thyroid cancer cells. Sci. Rep. 9, 7374 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Lan, L. et al. Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins. BMC Cancer 18, 809 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Clingman, C. C. et al. Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite. eLife 14, e02848 (2014).

    Article  Google Scholar 

  237. Law, J. H. et al. Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. PLoS One 5, 1–11 (2010).

    Article  Google Scholar 

  238. Sechi, M. et al. Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models. Sci. Rep. 8, 15726 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Tiwari, A. et al. Blocking y-box binding protein-1 through simultaneous targeting of PI3K and MAPK in triple negative breast cancers. Cancers 12, 1–19 (2020).

    Article  Google Scholar 

  240. Hasegawa, M. et al. A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis. Arthritis Rheum. 60, 3465–3475 (2009).

    Article  CAS  PubMed  Google Scholar 

  241. Ding, S., Xu, Y., Hao, T. & Ma, P. Partial least squares based gene expression analysis in renal failure. Diagn. Pathol. 9, 137 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  242. Täuber, H., Hüttelmaier, S. & Köhn, M. POLIII-derived non-coding RNAs acting as scaffolds and decoys. J. Mol. Cell Biol. 11, 880–885 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Liepelt, A. et al. Identification of RNA-binding proteins in macrophages by interactome capture. Mol. Cell. Proteom. 15, 2699–2714 (2016).

    Article  CAS  Google Scholar 

  244. Perez-Perri, J. I. et al. Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture. Nat. Commun. 9, 4408 (2018). This work represents an important addition to the current toolbox for RNA-interactome capture (RIC) using LNA-modified probes and allowing for RIC from tissue.

    Article  PubMed  PubMed Central  Google Scholar 

  245. Trendel, J. et al. The human RNA-binding proteome and its dynamics during translational arrest. Cell 176, 391–403.e19 (2019). One of the three key publications implementing organic phase extraction as a central technique exploiting the unique biophysical properties of crosslinked RNA-protein complexes to enrich and isolate RNPs.

    Article  CAS  PubMed  Google Scholar 

  246. Backlund, M. et al. Plasticity of nuclear and cytoplasmic stress responses of RNA-binding proteins. Nucleic Acids Res. 48, 4725–4740 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Perez-Perri, J. I. et al. Global analysis of RNA-binding protein dynamics by comparative and enhanced RNA interactome capture. Nat. Protoc. 16, 27–60 (2021).

    Article  CAS  PubMed  Google Scholar 

  248. Liao, Y. et al. The cardiomyocyte RNA-binding proteome: links to intermediary metabolism and heart disease. Cell Rep. 16, 1456–1469 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Castello, A. et al. Comprehensive identification of RNA-binding domains in human cells. Mol. Cell 63, 696–710 (2016). Key study establishing a technique to identify RNA-binding domains in global RPBomes by partial tryptic digest.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Urdaneta, E. C. et al. Purification of cross-linked RNA-protein complexes by phenol-toluol extraction. Nat. Commun. 10, 990 (2019). One of the three key publications implementing organic phase extraction as a central technique exploiting the unique biophysical properties of crosslinked RNA-protein complexes to enrich and isolate RNPs.

    Article  PubMed  PubMed Central  Google Scholar 

  251. Queiroz, R. M. L. et al. Comprehensive identification of RNA–protein interactions in any organism using orthogonal organic phase separation (OOPS). Nat. Biotechnol. 37, 169–178 (2019). One of the three key publications implementing organic phase extraction as a central technique exploiting the unique biophysical properties of crosslinked RNA-protein complexes to enrich and isolate RNPs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Michael Ignarski, Roman-Ulrich Müller.

Authors and Affiliations

  1. Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

    Lisa Seufert, Thomas Benzing, Michael Ignarski & Roman-Ulrich Müller

  2. CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

    Lisa Seufert, Thomas Benzing, Michael Ignarski & Roman-Ulrich Müller

Authors
  1. Lisa Seufert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Benzing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Ignarski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roman-Ulrich Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.S., R.-U.M. and M.I. researched the data and wrote the article. R.-U.M., T.B. and M.I. reviewed or edited the manuscript before submission. All authors made substantial contributions to discussions of the content.

Corresponding authors

Correspondence to Michael Ignarski or Roman-Ulrich Müller.

Ethics declarations

Competing interests

R.-U.M. has received honoraria for counselling and participation in advisory boards from Alnylam Pharmaceuticals. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Nephrology thanks Daniel Constam, Zheng Dong and Johan Lorenzen for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

MiRNA sponges

Transcripts (for example, circRNAs) that contain multiple complementary sites that bind and sequester specific miRNAs to prevent them from interacting with their target RNAs.

Protein sponges

Transcripts (for example, circRNAs) that sequester proteins to withdraw them from the cellular pool and thereby influence their cellular functions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seufert, L., Benzing, T., Ignarski, M. et al. RNA-binding proteins and their role in kidney disease. Nat Rev Nephrol 18, 153–170 (2022). https://doi.org/10.1038/s41581-021-00497-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-021-00497-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing