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RNA-binding proteins and their role in kidney disease

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.

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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.

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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.

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Correspondence to Michael Ignarski or Roman-Ulrich Müller.

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

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

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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.

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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

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