Review Article | Published:

A brave new world of RNA-binding proteins

Nature Reviews Molecular Cell Biology volume 19, pages 327341 (2018) | Download Citation

Abstract

RNA-binding proteins (RBPs) are typically thought of as proteins that bind RNA through one or multiple globular RNA-binding domains (RBDs) and change the fate or function of the bound RNAs. Several hundred such RBPs have been discovered and investigated over the years. Recent proteome-wide studies have more than doubled the number of proteins implicated in RNA binding and uncovered hundreds of additional RBPs lacking conventional RBDs. In this Review, we discuss these new RBPs and the emerging understanding of their unexpected modes of RNA binding, which can be mediated by intrinsically disordered regions, protein–protein interaction interfaces and enzymatic cores, among others. We also discuss the RNA targets and molecular and cellular functions of the new RBPs, as well as the possibility that some RBPs may be regulated by RNA rather than regulate RNA.

Key points

  • Novel proteome-wide approaches, in particular RNA interactome capture, have largely expanded the repertoire of known RNA-binding proteins (RBPs)

  • Newly discovered RBPs generally lack canonical RNA-binding domains (RBDs) and are functionally diverse. These unconventional RBPs are conserved from yeast to humans and respond to environmental and physiological cues

  • A variety of protein domains endowed with RNA-binding activity have recently been discovered, including DNA-binding domains, protein–protein interaction interfaces, enzymatic cores and intrinsically disordered regions. These domains are prone to post-translational modifications and represent disease mutation hot spots

  • The identification of unconventional RBPs and their unconventional RBDs suggests the existence of previously unidentified modes of RNA binding and new biological functions for protein–RNA interactions

  • RNA control of protein function may occur more commonly than previously anticipated

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Messenger-RNA-binding proteins and the messages they carry. Nat. Rev. Mol. Cell Biol. 3, 195–205 (2002).

  2. 2.

    , & RNA-binding proteins: modular design for efficient function. Nat. Rev. Mol. Cell Biol. 8, 479–490 (2007).

  3. 3.

    , & RNA recognition motifs: boring? Not quite. Curr. Opin. Struct. Biol. 18, 290–298 (2008).

  4. 4.

    , & Structure and function of KH domains. FEBS J. 275, 2712–2726 (2008).

  5. 5.

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

  6. 6.

    The ribosome emerges from a black box. Cell 159, 979–984 (2014).

  7. 7.

    A structural understanding of the dynamic ribosome machine. Nat. Rev. Mol. Cell Biol. 9, 242–253 (2008).

  8. 8.

    et al. Structural snapshots of actively translating human ribosomes. Cell 161, 845–857 (2015).

  9. 9.

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

  10. 10.

    & The Spliceosome: The Ultimate RNA Chaperone and Sculptor. Trends Biochem. Sci. 41, 33–45 (2016).

  11. 11.

    , & Structure of a pre-catalytic spliceosome. Nature 546, 617–621 (2017).

  12. 12.

    & Specificity and nonspecificity in RNA-protein interactions. Nat. Rev. Mol. Cell Biol. 16, 533–544 (2015).

  13. 13.

    , & From cis-regulatory elements to complex RNPs and back. Cold Spring Harb. Perspect. Biol. 4, a012245 (2012).

  14. 14.

    , , & The clothes make the mRNA: past and present trends in mRNP fashion. Annu. Rev. Biochem. 84, 325–354 (2015).

  15. 15.

    & Emerging roles for ribonucleoprotein modification and remodeling in controlling RNA fate. Trends Cell Biol. 23, 504–510 (2013).

  16. 16.

    & Emerging mechanisms of mRNP remodeling regulation. Wiley Interdiscip Rev. RNA 5, 713–722 (2014).

  17. 17.

    & RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat. Rev. Mol. Cell Biol. 10, 430–436 (2009).

  18. 18.

    mRNP granules. Assembly, function, and connections with disease. RNA Biol. 11, 1019–1030 (2014).

  19. 19.

    & Principles and properties of stress granules. Trends Cell Biol. 26, 668–679 (2016).

  20. 20.

    & Intrinsically disordered proteins in cellular signalling and regulation. Nat. Rev. Mol. Cell Biol. 16, 18–29 (2015).

  21. 21.

    & The specificity of long noncoding RNA expression. Biochim. Biophys. Acta 1859, 16–22 (2016).

  22. 22.

    & RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat. Rev. Mol. Cell Biol. 14, 699–712 (2013).

  23. 23.

    & The structure, function and evolution of proteins that bind DNA and RNA. Nat. Rev. Mol. Cell Biol. 15, 749–760 (2014).

  24. 24.

    & The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157, 77–94 (2014).

  25. 25.

    , & The expanding universe of ribonucleoproteins: of novel RNA-binding proteins and unconventional interactions. Pflugers Arch. 468, 1029–1040 (2016).

  26. 26.

    , & Deciphering the mRNP code: RNA-bound determinants of post-transcriptional gene regulation. Trends Biochem. Sci. 42, 369–382 (2017).

  27. 27.

    The organization and regulation of mRNA-protein complexes. Wiley Interdiscip. Rev. RNA 8, 1369 (2017).

  28. 28.

    & How cells get the message: dynamic assembly and function of mRNA-protein complexes. Nat. Rev. Genet. 14, 275–287 (2013).

  29. 29.

    , , & Determinants of affinity and specificity in RNA-binding proteins. Curr. Opin. Struct. Biol. 38, 83–91 (2016).

  30. 30.

    & Homology between IRE-BP, a regulatory RNA-binding protein, aconitase, and isopropylmalate isomerase. Nucleic Acids Res. 19, 1739–1740 (1991).

  31. 31.

    , , , & Structural relationship between an iron-regulated RNA-binding protein (IRE-BP) and aconitase: functional implications. Cell 64, 881–883 (1991).

  32. 32.

    et al. Identification of an RNA binding site for human thymidylate synthase. Proc. Natl Acad. Sci. USA 90, 517–521 (1993).

  33. 33.

    Enzymes as RNA-binding proteins: a role for (di)nucleotide-binding domains? Trends Biochem. Sci. 19, 101–103 (1994).

  34. 34.

    , , & Unbiased RNA-protein interaction screen by quantitative proteomics. Proc. Natl Acad. Sci. USA 106, 10626–10631 (2009).

  35. 35.

    , , & A screen for RNA-binding proteins in yeast indicates dual functions for many enzymes. PLoS ONE 5, e15499 (2010).

  36. 36.

    , , & Proteome-wide search reveals unexpected RNA-binding proteins in Saccharomyces cerevisiae. PLoS ONE 5, e12671 (2010).

  37. 37.

    et al. A compendium of RNA-binding proteins that regulate microRNA biogenesis. Mol. Cell 66, 270–284.e13 (2017).

  38. 38.

    et al. System-wide identification of RNA-binding proteins by interactome capture. Nat. Protoc. 8, 491–500 (2013).

  39. 39.

    et al. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell 46, 674–690 (2012). This is one of the two pioneer RIC studies. In this work, RIC was applied to HEK293 cells identifying 791 RBPs, many of which were previously not known to bind RNA.

  40. 40.

    et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012). This is also one of the two pioneer RIC studies. In this work, RIC was applied to HeLa cells identifying 860 RBPs, many of which were previously not known to bind RNA.

  41. 41.

    , , & RNA-binding proteins in Mendelian disease. Trends Genet. 29, 318–327 (2013).

  42. 42.

    , , , & A versatile assay for RNA-binding proteins in living cells. RNA 20, 721–731 (2014).

  43. 43.

    et al. Photo-cross-linking and high-resolution mass spectrometry for assignment of RNA-binding sites in RNA-binding proteins. Nat. Methods 11, 1064–1070 (2014). This article presents the development of a method that assigns RNA-binding sites within RBPs by direct identification of peptides crosslinked to a nucleotide.

  44. 44.

    et al. The RNA-binding proteomes from yeast to man harbour conserved enigmRBPs. Nat. Commun. 6, 10127 (2015). RIC was applied in this study to human hepatoma cells (HuH7) and S. cerevisiae. The RNA targets of one of the discovered RBPs, HSD17B10, were identified by iCLIP. This protein binds mitochondrial tRNAs, and a mutation-causing disease abrogates the interaction with RNA.

  45. 45.

    et al. Comprehensive identification of RNA-binding domains in human cells. Mol. Cell 63, 696–710 (2016). This article describes RBDmap, a method for proteome-wide identification of RBDs. Applied to HeLa cells, RBDmap revealed 1,174 RNA-binding sites in 529 RBPs.

  46. 46.

    et al. The RNA-binding protein repertoire of embryonic stem cells. Nat. Struct. Mol. Biol. 20, 1122–1130 (2013).

  47. 47.

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

  48. 48.

    et al. Identification of RNA-binding proteins in macrophages by interactome capture. Mol. Cell Proteom. 15, 2699–2674 (2016).

  49. 49.

    , , & Global analysis of yeast mRNPs. Nat. Struct. Mol. Biol. 20, 127–133 (2013).

  50. 50.

    , & Conserved mRNA-binding proteomes in eukaryotic organisms. Nat. Struct. Mol. Biol. 22, 1027–1033 (2015).

  51. 51.

    et al. Comprehensive identification of mRNA-binding proteins of Leishmania donovani by interactome capture. PLoS ONE 12, e0170068 (2017).

  52. 52.

    et al. The mRNA-bound proteome of the human malaria parasite Plasmodium falciparum. Genome Biol. 17, 147 (2016).

  53. 53.

    , , , & Gene expression regulatory networks in Trypanosoma brucei: insights into the role of the mRNA-binding proteome. Mol. Microbiol. 100, 457–471 (2016).

  54. 54.

    , , , & The RNA-binding protein repertoire of Arabidopsis thaliana. Sci. Rep. 6, 29766 (2016).

  55. 55.

    et al. In Planta Determination of the mRNA-Binding Proteome of Arabidopsis Etiolated Seedlings. Plant Cell 28, 2435–2452 (2016).

  56. 56.

    et al. UV crosslinked mRNA-binding proteins captured from leaf mesophyll protoplasts. Plant Methods 12, 42 (2016).

  57. 57.

    et al. Global changes of the RNA-bound proteome during the maternal-to-zygotic transition in Drosophila. Nat. Commun. 7, 12128 (2016). This study is the first quantitative RIC analysis to detect differential RBP activity. Here, 116 'dynamic' RBPs were identified during D. melanogaster early embryogenesis.

  58. 58.

    et al. The mRNA-bound proteome of the early fly embryo. Genome Res. 26, 1000–1009 (2016).

  59. 59.

    et al. Dynamic RNA-protein interactions underlie the zebrafish maternal-to-zygotic transition. Genome Res. 27, 1184–1194 (2017).

  60. 60.

    & InParanoid 8: orthology analysis between 273 proteomes, mostly eukaryotic. Nucleic Acids Res. 43, D234–D239 (2015).

  61. 61.

    , & Inparanoid: a comprehensive database of eukaryotic orthologs. Nucleic Acids Res. 33, D476–D480 (2005).

  62. 62.

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

  63. 63.

    , & Messenger RNA modifications: form, distribution, and function. Science 352, 1408–1412 (2016).

  64. 64.

    & Translating the epitranscriptome. Wiley Interdiscip. Rev. RNA 8, e1375 (2017).

  65. 65.

    Metabolic enzymes that bind RNA: yet another level of cellular regulatory network? Acta Biochim. Pol. 53, 11–32 (2006).

  66. 66.

    & The REM phase of gene regulation. Trends Biochem. Sci. 35, 423–426 (2010).

  67. 67.

    , & Metabolic enzymes enjoying new partnerships as RNA-binding proteins. Trends Endocrinol. Metab. 26, 746–757 (2015).

  68. 68.

    & The role of thymidylate synthase as an RNA binding protein. Bioessays 18, 191–198 (1996).

  69. 69.

    et al. Thymidylate synthase as a translational regulator of cellular gene expression. Biochim. Biophys. Acta 1587, 174–182 (2002).

  70. 70.

    , & A census of human RNA-binding proteins. Nat. Rev. Genet. 15, 829–845 (2014). This study used a data mining approach to compile a catalogue of RBPs employing domain composition and known roles of proteins to classify them as RBPs.

  71. 71.

    , , & Structure of eIF3b RNA recognition motif and its interaction with eIF3j: structural insights into the recruitment of eIF3b to the 40 S ribosomal subunit. J. Biol. Chem. 282, 8165–8174 (2007).

  72. 72.

    , , & The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell 126, 713–725 (2006).

  73. 73.

    et al. Quantitative proteomic analysis reveals concurrent RNA-protein interactions and identifies new RNA-binding proteins in Saccharomyces cerevisiae. Genome Res. 23, 1028–1038 (2013).

  74. 74.

    et al. SONAR Discovers RNA-Binding Proteins from Analysis of Large-Scale Protein-Protein Interactomes. Mol. Cell 64, 282–293 (2016). SONAR uses protein–protein interaction databases to predict potential RBPs by exploiting the tendency of RBPs to interact with other RBPs.

  75. 75.

    et al. Resources for the Comprehensive Discovery of Functional RNA Elements. Mol. Cell 61, 903–913 (2016).

  76. 76.

    et al. The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 162, 425–440 (2015).

  77. 77.

    et al. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol. Cell 32, 371–382 (2008).

  78. 78.

    et al. Two-site phosphorylation of EPRS coordinates multimodal regulation of noncanonical translational control activity. Mol. Cell 35, 164–180 (2009).

  79. 79.

    , , , & Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control. Proc. Natl Acad. Sci. USA 108, 1415–1420 (2011).

  80. 80.

    et al. Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite. eLife 3, e02848 (2014).

  81. 81.

    & eIF4G dramatically enhances the binding of eIF4E to the mRNA 5′-cap structure. J. Biol. Chem. 272, 21677–21680 (1997).

  82. 82.

    & dsRNA-dependent protein kinase PKR and its role in stress, signaling and HCV infection. Viruses 4, 2598–2635 (2012).

  83. 83.

    & Cytoplasmic sensing of viral nucleic acids. Curr. Opin. Virol. 11, 31–37 (2015).

  84. 84.

    RNA sensing: the more RIG-I the merrier? EMBO Rep. 14, 751–752 (2013).

  85. 85.

    et al. Label-free protein-RNA interactome analysis identifies Khsrp signaling downstream of the p38/Mk2 kinase complex as a critical modulator of cell cycle progression. PLoS ONE 10, e0125745 (2015).

  86. 86.

    Posttranscriptional regulation in Drosophila oocytes and early embryos. Wiley Interdiscip. Rev. RNA 2, 408–416 (2011).

  87. 87.

    et al. Identification of novel non-canonical RNA-binding sites in Gemin5 involved in internal initiation of translation. Nucleic Acids Res. 42, 5742–5754 (2014).

  88. 88.

    , & Investigation of protein-RNA interactions by mass spectrometry — techniques and applications. J. Proteom. 75, 3478–3494 (2012).

  89. 89.

    & Glyceraldehyde-3-phosphate dehydrogenase selectively binds AU-rich RNA in the NAD+-binding region (Rossmann fold). J. Biol. Chem. 270, 2755–2763 (1995).

  90. 90.

    et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

  91. 91.

    , , & Specifying RNA-binding regions in proteins by peptide cross-linking and affinity purification. J. Proteome Res. 16, 2762–2772 (2017).

  92. 92.

    et al. High-resolution mapping of RNA-binding regions in the nuclear proteome of embryonic stem cells. Mol. Cell 64, 416–430 (2016). This study used a proteomic-based method to assign RNA-binding sites to RBPs by identifying peptides for which the intensity is reduced after ultraviolet irradiation. The study detected 1,475 RNA-binding sites mapping to 803 proteins.

  93. 93.

    et al. Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA. Genes Dev. 24, 2615–2620 (2010).

  94. 94.

    , , , & Nascent RNA interaction keeps PRC2 activity poised and in check. Genes Dev. 28, 1983–1988 (2014).

  95. 95.

    , , , & PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells. Nat. Struct. Mol. Biol. 20, 1258–1264 (2013).

  96. 96.

    et al. A compendium of RNA-binding motifs for decoding gene regulation. Nature 499, 172–177 (2013).

  97. 97.

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

  98. 98.

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

  99. 99.

    et al. Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat. Methods 13, 508–514 (2016). This study used an enhanced version of the iCLIP method as well as ultraviolet crosslinking, RNase treatment and RNA sequencing to determine the binding sites of RBPs across the cellular transcriptome. This has been applied to many RBPs under the same experimental conditions, offering a rich source of information on protein–RNA interactions.

  100. 100.

    et al. RNA Bind-n-Seq: quantitative assessment of the sequence and structural binding specificity of RNA binding proteins. Mol. Cell 54, 887–900 (2014).

  101. 101.

    & The “Observer Effect” in genome-wide surveys of protein-RNA interactions. Mol. Cell 49, 601–604 (2013).

  102. 102.

    , , & CWC22 connects pre-mRNA splicing and exon junction complex assembly. Cell Rep. 2, 454–461 (2012).

  103. 103.

    et al. Insights into the design and interpretation of iCLIP experiments. Genome Biol. 18, 7 (2017).

  104. 104.

    , , & The new (dis)order in RNA regulation. Cell Commun. Signal 14, 9 (2016).

  105. 105.

    & A structural perspective of RNA recognition by intrinsically disordered proteins. Cell. Mol. Life Sci. 73, 4075–4084 (2016).

  106. 106.

    , , & Defining the RGG/RG motif. Mol. Cell 50, 613–623 (2013).

  107. 107.

    et al. Structure-function studies of FMRP RGG peptide recognition of an RNA duplex-quadruplex junction. Nat. Struct. Mol. Biol. 18, 796–804 (2011).

  108. 108.

    et al. Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149, 768–779 (2012).

  109. 109.

    et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).

  110. 110.

    , & Searching DNA via a “Monkey Bar” mechanism: the significance of disordered tails. J. Mol. Biol. 396, 674–684 (2010).

  111. 111.

    , & The arginine-rich RNA-binding motif of HIV-1 Rev is intrinsically disordered and folds upon RRE binding. Biophys. J. 105, 1004–1017 (2013).

  112. 112.

    et al. Aptamers and the RNA world, past and present. Cold Spring Harb. Perspect. Biol. 4, a003582 (2012).

  113. 113.

    , , , & Direct functional interaction of initiation factor eIF4G with type 1 internal ribosomal entry sites. Proc. Natl Acad. Sci. USA 106, 9197–9202 (2009).

  114. 114.

    , , , & Specific interaction of eukaryotic translation initiation factor 3 with the 5′ nontranslated regions of hepatitis C virus and classical swine fever virus RNAs. J. Virol. 72, 4775–4782 (1998).

  115. 115.

    , , , & Cryo-EM structure of Hepatitis C virus IRES bound to the human ribosome at 3.9-A resolution. Nat. Commun. 6, 7646 (2015).

  116. 116.

    , & Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat. Rev. Mol. Cell Biol. (2017).

  117. 117.

    et al. An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol. Cell 33, 717–726 (2009).

  118. 118.

    et al. Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc. Natl Acad. Sci. USA 88, 8977–8981 (1991).

  119. 119.

    , , & Red carpet for iron metabolism. Cell 168, 344–361 (2017).

  120. 120.

    et al. Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science 314, 1903–1908 (2006).

  121. 121.

    , , & The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal. 23, 317–323 (2011).

  122. 122.

    et al. Glyceraldehyde-3- phosphate dehydrogenase regulates endothelin-1 expression by a novel, redox-sensitive mechanism involving mRNA stability. Mol. Cell. Biol. 28, 7139–7155 (2008).

  123. 123.

    & The protein acetylome and the regulation of metabolism. Trends Plant Sci. 17, 423–430 (2012).

  124. 124.

    , & Intersections of post-transcriptional gene regulatory mechanisms with intermediary metabolism. Biochim. Biophys. Acta 1860, 349–362 (2017).

  125. 125.

    & Probing RNA-protein networks: biochemistry meets genomics. Trends Biochem. Sci. 40, 157–164 (2015).

  126. 126.

    , , & Protein-RNA interactions: new genomic technologies and perspectives. Nat. Rev. Genet. 13, 77–83 (2011).

  127. 127.

    et al. A large-scale binding and functional map of human RNA binding proteins. bioRxiv, 179648 (2017).

  128. 128.

    , , & Functional splicing network reveals extensive regulatory potential of the core spliceosomal machinery. Mol. Cell 57, 7–22 (2015).

  129. 129.

    , & Genome-wide identification of Fas/CD95 alternative splicing regulators reveals links with iron homeostasis. Mol. Cell 57, 23–38 (2015).

  130. 130.

    et al. Trim25 is an RNA-specific activator of Lin28a/TuT4-mediated uridylation. Cell Rep. 9, 1265–1272 (2014).

  131. 131.

    et al. Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness. Science 350, 217–221 (2015). This work shows that the XRN1-generated, subgenomic RNA of dengue virus interferes with IFNβ induction by sequestering TRIM25, preventing the ubiquitination of RIGI by this protein.

  132. 132.

    et al. RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC Biol. 15, 105 (2017). In this paper, TRIM25 target RNAs are uncovered by CLIP analysis. TRIM25 displays a preference for guanine-rich tracks present at the 3′ UTR of hundreds of mRNAs. TRIM25 E3 ubiquitin ligase activity is stimulated in the interaction with RNA.

  133. 133.

    et al. mRNA export through an additional cap-binding complex consisting of NCBP1 and NCBP3. Nat. Commun. 6, 8192 (2015). In this study, NCBP3 mediates RNA export through its interaction with NCBP1 following a similar mechanism as NCBP2. NCBP3 is an RBP newly discovered by the RIC studies.

  134. 134.

    et al. FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation. RNA 21, 1873–1884 (2015). This work provides an iCLIP analysis of the noncanonical RBP FASTKD2, showing that FASTKD2 binds mitochondrial RNAs and regulates their metabolism.

  135. 135.

    , , & An RNA-binding atypical tropomyosin recruits kinesin-1 dynamically to oskar mRNPs. EMBO J. 36, 319–333 (2017).

  136. 136.

    et al. Roles of 17beta-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders. J. Steroid Biochem. Mol. Biol. 143, 460–472 (2014).

  137. 137.

    et al. A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO Mol. Med. 2, 51–62 (2010).

  138. 138.

    et al. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. Cell 135, 462–474 (2008).

  139. 139.

    & Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex. Nucleic Acids Res. 43, 6649 (2015).

  140. 140.

    & Mitochondrial RNA granules are centers for posttranscriptional rna processing and ribosome biogenesis. Cell Rep. 10, 920–932 (2015).

  141. 141.

    et al. FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am. J. Hum. Genet. 83, 415–423 (2008).

  142. 142.

    , & Mechanism of Dis3l2 substrate recognition in the Lin28-let-7 pathway. Nature 514, 252–256 (2014).

  143. 143.

    et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920 (2007).

  144. 144.

    et al. The structural basis of pathogenic subgenomic flavivirus RNA (sfRNA) production. Science 344, 307–310 (2014).

  145. 145.

    et al. Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. Science 353, 1549–1552 (2016). This study finds that cyclin A2 directly binds the 3′ UTR of the MRE11 mRNA (marked with arrows) to promote MRE11 mRNA translation.

  146. 146.

    , & Crosslinking proteins to nucleic acids by ultraviolet laser irradiation. Trends Biochem. Sci. 16, 323–326 (1991).

  147. 147.

    et al. CRISPR/Cas9-mediated integration enables TAG-eCLIP of endogenously tagged RNA binding proteins. Methods 118, 50–59 (2016).

  148. 148.

    et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399 (2015).

  149. 149.

    et al. Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594 (2015).

  150. 150.

    et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014).

  151. 151.

    et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 16, 191–198 (2014).

  152. 152.

    et al. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).

  153. 153.

    et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015).

  154. 154.

    et al. m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 542, 475–478 (2017).

  155. 155.

    et al. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560–564 (2015).

  156. 156.

    , , , & UpSet: visualization of intersecting sets. IEEE Trans. Vis. Comput. Graph. 20, 1983–1992 (2014).

  157. 157.

    , & Conducting the initiation of protein synthesis: the role of eIF4G. Biol. Cell 95, 141–156 (2003).

  158. 158.

    & PKR in innate immunity, cancer, and viral oncolysis. Methods Mol. Biol. 383, 277–301 (2007).

Download references

Acknowledgements

The authors dedicate this Review to the memory of B. Fischer, who sadly passed away while this Review was in preparation. The authors are grateful to the members of their laboratories for helpful discussions throughout. The authors also acknowledge research funding from the European Research Council (ERC-2011-ADG_20110310; M.W.H.), a UK Medical Research Council Career Development Award (MR/L019434/1; A.C), the European Molecular Biology Laboratory Interdisciplinary Postdoctoral 2 Programme (EIPOD2/291772; T.S.) and the Australian National Health and Medical Research Council (APP1120483; M.W.H. and T.P.).

Author information

Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

    • Matthias W. Hentze
    •  & Thomas Schwarzl
  2. Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK

    • Alfredo Castello
  3. European Molecular Biology Laboratory–Australia Collaborating Group, Department of Genome Sciences, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra) Australian Capital Territory 2601, Australia.

    • Thomas Preiss
  4. Victor Chang Cardiac Research Institute, Darlinghurst (Sydney), New South Wales 2010, Australia.

    • Thomas Preiss

Authors

  1. Search for Matthias W. Hentze in:

  2. Search for Alfredo Castello in:

  3. Search for Thomas Schwarzl in:

  4. Search for Thomas Preiss in:

Contributions

All authors researched data for the article, made substantial contributions to the discussion of content, wrote the article and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Matthias W. Hentze or Thomas Preiss.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (figure)

    Comparison of RNA interactome capture data with in silico methods to identify RNA-binding proteins (RBPs).

Excel files

  1. 1.

    Supplementary information S2 (table)

    This table contains high-throughput detection screens for RNA-binding proteins

Glossary

RNA recognition motif

(RRM). An RNA-binding domain of 90 amino acids that folds into two α-helices packed against a four-stranded β-sheet, which interact with RNA.

hnRNP K homology domain

(KH). An RNA-binding domain of 70 amino acids that folds into three α-helices packed against a three-stranded β-sheet. RNA binds to a hydrophobic cleft formed between two core α-helices and a GXXG loop that interconnects them.

DEAD box helicase

RNA helicases with two highly similar domains that resemble the bacterial recombinase A and contain the conserved sequence Asp-Glu-Ala-Asp (DEAD). RNA binds across both helicase domains.

Epitranscriptome

The collective, chemically diverse RNA modifications found in a transcriptome. Many of the modifications serve regulatory roles.

Cajal bodies

Subnuclear membrane-less structures involved in multiple aspects of nuclear RNA metabolism.

Paraspeckles

Ribonucleoprotein particles of poorly defined function in the nucleoplasm of mammalian cells.

Processing (P) bodies

Microscopically visible foci in the cytoplasm of eukaryotic cells that contain mRNAs and mRNA silencing and turnover factors.

Stress granules

Cytoplasmic aggregates of stalled translation initiation complexes in eukaryotic cells that are induced by different forms of cellular stress.

Liquid–liquid phase separation

A (bio)physical process whereby membrane-less compartments are formed within cells as phase-separated, liquid-like droplets.

Intrinsically disordered regions

(IDRs). Areas within native proteins that lack stable secondary or tertiary structure and thus appear unfolded.

Long non-coding RNAs

(lncRNAs). RNAs longer than 200 nucleotides without annotated protein-coding potential.

Ultraviolet crosslinking

A method that uses ultraviolet light irradiation in vitro or in living cells to covalently connect proteins and RNA that are positioned in very close proximity to each other.

Zinc-finger domains

Zinc-binding protein domains that can mediate interactions with DNA, RNA or proteins, depending on their subclass.

Intermediary metabolism

A collective term for metabolic processes that convert nutrients into cellular components.

InParanoid analysis

A method for detecting orthologues and in-paralogue gene clusters across different, often distant species.

UpSet plot

A plot used to visualize the total size and overlaps of various data sets.

BioPlex PPI data set

A comprehensive collection of protein–protein interaction networks generated by experimental approaches.

Maternal-to-zygotic transition

(MZT). The phase in embryonic development during which control by maternally derived factors ceases and the zygotic genome is activated.

Electrophoretic mobility shift assay

(EMSA). A method to study protein–nucleic acid interactions in vitro by resolving a labelled nucleic acid probe and its binding proteins on the basis of the reduced mobility of the probe–protein complexes through a nondenaturing gel.

RNPxl

Custom-designed software to facilitate the identification of mass spectra derived from a peptide crosslinked to a nucleotide.

G-Quadruplexes

Nucleic acid structures made of two or more stacks of planar arrays of four guanine bases.

RNA aptamers

Relatively short and often highly folded RNA molecules, which are selected for specific, high-affinity interactions with proteins or other molecules.

Rossmann-fold

(R-f). A protein domain with up to seven mostly parallel β-strands combined with connecting α-helices. Typically found in proteins that bind nucleotides.

RNase P complex

An RNase complex that processes precursor tRNA.

Speckles

Nucleoplasmic granules located at interchromatin regions that are enriched in splicing factors

Polyuridylation

The addition of multiple uridines to the 3′ end of RNA molecules by uridylyltransferases as a signal for RNA degradation.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrm.2017.130