The hnRNP family: insights into their role in health and disease

Anantha RW, Alcivar AL, Ma J et al (2013) Requirement of heterogeneous nuclear ribonucleoprotein C for BRCA gene expression and homologous recombination. PLoS One 8:e61368. doi:10.1371/journal.pone.0061368 Bekenstein U, Soreq H (2013) Heterogeneous nuclear ribonucleoprotein A1 in health and neurodegenerative disease: from structural insights to post-transcriptional regulatory roles. Mol Cell Neurosci 56:436–446. doi:10.1016/j.mcn.2012.12.002 Beyer AL, Christensen ME, Walker BW, LeStourgeon WM (1977) Identification and characterization of the packaging proteins of core 40S hnRNP particles. Cell 11:127–138 Bi H, Yang X, Yuan J et al (2013) H19 inhibits RNA polymerase II-mediated transcription by disrupting the hnRNP U-actin complex. Biochim Biophys Acta 1830:4899–4906. doi:10.1016/j.bbagen.2013.06.026 Blanchette AR, Fuentes Medel YF, Gardner PD (2006) Cell-type-specific and developmental regulation of heterogeneous nuclear ribonucleoprotein K mRNA in the rat nervous system. Gene Expr Patterns 6:596–606. doi:10.1016/j.modgep.2005.11.008 Bomsztyk K, Denisenko O, Ostrowski J (2004) hnRNP K: one protein multiple processes. BioEssays 26:629–638. doi:10.1002/bies.20048 Borreca A, Gironi K, Amadoro G, Ammassari-Teule M (2015) Opposite dysregulation of fragile-X mental retardation protein and heteronuclear ribonucleoprotein C protein associates with enhanced APP translation in Alzheimer disease. Mol Neurobiol. doi:10.1007/s12035-015-9229-8 Bushell M, Stoneley M, Kong YW et al (2006) Polypyrimidine tract binding protein regulates IRES-mediated gene expression during apoptosis. Mol Cell 23:401–412. doi:10.1016/j.molcel.2006.06.012 Cao W, Razanau A, Feng D et al (2012) Control of alternative splicing by forskolin through hnRNP K during neuronal differentiation. Nucleic Acids Res 40:8059–8071. doi:10.1093/nar/gks504 Cartegni L, Maconi M, Morandi E et al (1996) hnRNP A1 selectively interacts through its Gly-rich domain with different RNA-binding proteins. J Mol Biol 259:337–348. doi:10.1006/jmbi.1996.0324 Chaudhury A, Chander P, Howe PH (2010a) Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: focus on hnRNP E1’s multifunctional regulatory roles. RNA 16:1449–1462. doi:10.1261/rna.2254110 Chaudhury A, Hussey GS, Ray PS et al (2010b) TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol 12:286–293. doi:10.1038/ncb2029 Chen H-H, Chang J-G, Lu R-M et al (2008) The RNA binding protein hnRNP Q modulates the utilization of exon 7 in the survival motor neuron 2 (SMN2) gene. Mol Cell Biol 28:6929–6938. doi:10.1128/MCB.01332-08 Chkheidze AN, Liebhaber SA (2003) A novel set of nuclear localization signals determine distributions of the αCP RNA-binding proteins. Society 23:8405–8415. doi:10.1128/MCB.23.23.8405 Cho S-J, Jung Y-S, Chen X (2013) Poly (C)-binding protein 1 regulates p63 expression through mRNA stability. PLoS One 8:e71724. doi:10.1371/journal.pone.0071724 Cho S, Moon H, Loh TJ et al (2014) hnRNP M facilitates exon 7 inclusion of SMN2 pre-mRNA in spinal muscular atrophy by targeting an enhancer on exon 7. Biochim Biophys Acta 1839:306–315. doi:10.1016/j.bbagrm.2014.02.006 Choi YD, Grabowski PJ, Sharp PA, Dreyfuss G (1986) Heterogeneous nuclear ribonucleoproteins: role in RNA splicing. Science 231:1534–1539 Choi HS, Song KY, Hwang CK et al (2008) A proteomics approach for identification of single strand DNA-binding proteins involved in transcriptional regulation of mouse mu opioid receptor gene. Mol Cell Proteom 7:1517–1529. doi:10.1074/mcp.M800052-MCP200 Cieniková Z, Jayne S, Damberger FF et al (2015) Evidence for cooperative tandem binding of hnRNP C RRMs in mRNA processing. RNA 21:1931–1942. doi:10.1261/rna.052373.115 Collier B, Goobar-Larsson L, Sokolowski M, Schwartz S (1998) Translational inhibition in vitro of human papillomavirus type 16 L2 mRNA mediated through interaction with heterogenous ribonucleoprotein K and poly(rC)-binding proteins 1 and 2. J Biol Chem 273:22648–22656 Cooper-Knock J, Higginbottom A, Stopford MJ et al (2015) Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol 130:63–75. doi:10.1007/s00401-015-1429-9 de López Silanes I, Stagno d’Alcontres M, Blasco MA (2010) TERRA transcripts are bound by a complex array of RNA-binding proteins. Nat Commun 1:33. doi:10.1038/ncomms1032 Dery KJ, Gaur S, Gencheva M et al (2011) Mechanistic control of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) splice isoforms by the heterogeneous nuclear ribonuclear proteins hnRNP L, hnRNP A1, and hnRNP M. J Biol Chem 286:16039–16051. doi:10.1074/jbc.M110.204057 Dombert B, Sivadasan R, Simon CM et al (2014) Presynaptic localization of Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons. PLoS One 9:e110846. doi:10.1371/journal.pone.0110846 Dominguez C, Fisette J-F, Chabot B, Allain FH-T (2010) Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs. Nat Struct Mol Biol 17:853–861. doi:10.1038/nsmb.1814 Dreyfuss G, Philipson L, Mattaj IW (1988) Ribonucleoprotein particles in cellular processes. J Cell Biol 106:1419–1425 Dreyfuss G, Matunis MJ, Piñol-Roma S, Burd CG (1993) hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem 62:289–321. doi:10.1146/annurev.bi.62.070193.001445 Dreyfuss G, Kim VN, Kataoka N (2002) Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3:195–205. doi:10.1038/nrm760 Elliott DJ, Venables JP, Newton CS et al (2000) An evolutionarily conserved germ cell-specific hnRNP is encoded by a retrotransposed gene. Hum Mol Genet 9:2117–2124 Engels B, Jannot G, Remenyi J et al (2012) Polypyrimidine tract binding protein (hnRNP I) is possibly a conserved modulator of miRNA-mediated gene regulation. PLoS One 7:e33144. doi:10.1371/journal.pone.0033144 Enokizono Y, Konishi Y, Nagata K et al (2005) Structure of hnRNP D complexed with single-stranded telomere DNA and unfolding of the quadruplex by heterogeneous nuclear ribonucleoprotein D. J Biol Chem 280:18862–18870. doi:10.1074/jbc.M411822200 Evers MM, Toonen LJA, van Roon-Mom WMC (2015) Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv Drug Deliv Rev 87:90–103. doi:10.1016/j.addr.2015.03.008 Fan X, Xiong H, Wei J et al (2015) Cytoplasmic hnRNPK interacts with GSK3β and is essential for the osteoclast differentiation. Sci Rep 5:17732. doi:10.1038/srep17732 Fialcowitz EJ, Brewer BY, Keenan BP, Wilson GM (2005) A hairpin-like structure within an AU-rich mRNA-destabilizing element regulates trans-factor binding selectivity and mRNA decay kinetics. J Biol Chem 280:22406–22417. doi:10.1074/jbc.M500618200 Fukuda A, Nakadai T, Shimada M, Hisatake K (2009a) Heterogeneous nuclear ribonucleoprotein R enhances transcription from the naturally configured c-fos promoter in vitro. J Biol Chem 284:23472–23480. doi:10.1074/jbc.M109.013656 Fukuda T, Naiki T, Saito M, Irie K (2009b) hnRNP K interacts with RNA binding motif protein 42 and functions in the maintenance of cellular ATP level during stress conditions. Genes Cells 14:113–128. doi:10.1111/j.1365-2443.2008.01256.x Gallardo M, Lee HJ, Zhang X et al (2015) hnRNP K iIs a haploinsufficient tumor suppressor that regulates proliferation and differentiation programs in hematologic malignancies. Cancer Cell 28:486–499. doi:10.1016/j.ccell.2015.09.001 Gamarnik AV, Andino R (1997) Two functional complexes formed by KH domain containing proteins with the 5′ noncoding region of poliovirus RNA. RNA 3:882–892 Gao Y, Tatavarty V, Korza G et al (2008) Multiplexed dendritic targeting of alpha calcium calmodulin-dependent protein kinase II, neurogranin, and activity-regulated cytoskeleton-associated protein RNAs by the A2 pathway. Mol Biol Cell 19:2311–2327. doi:10.1091/mbc.E07-09-0914 Gautrey H, Jackson C, Dittrich A-L et al (2015) SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells. RNA Biol 12:1139–1151. doi:10.1080/15476286.2015.1076610 Görlach M, Wittekind M, Beckman RA et al (1992) Interaction of the RNA-binding domain of the hnRNP C proteins with RNA. EMBO J 11:3289–3295 Grishin NV (2001) KH domain: one motif, two folds. Nucleic Acids Res 29:638–643. doi:10.1093/nar/29.3.638 Habelhah H, Shah K, Huang L et al (2001) ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation. Nat Cell Biol 3:325–330. doi:10.1038/35060131 Hadian K, Vincendeau M, Mäusbacher N et al (2009) Identification of a heterogeneous nuclear ribonucleoprotein-recognition region in the HIV Rev protein. J Biol Chem 284:33384–33391. doi:10.1074/jbc.M109.021659 Hamid FM, Makeyev EV (2014) Regulation of mRNA abundance by polypyrimidine tract-binding protein-controlled alternate 5′ splice site choice. PLoS Genet 10:e1004771. doi:10.1371/journal.pgen.1004771 Han SP, Tang YH, Smith R (2010) Functional diversity of the hnRNPs: past, present and perspectives. Biochem J 430:379–392. doi:10.1042/BJ20100396 Hasegawa Y, Brockdorff N, Kawano S et al (2010) The matrix protein hnRNP U is required for chromosomal localization of Xist RNA. Dev Cell 19:469–476. doi:10.1016/j.devcel.2010.08.006 Hoek KS, Kidd GJ, Carson JH, Smith R (1998) hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA. Biochemistry 37:7021–7029. doi:10.1021/bi9800247 Hovhannisyan RH, Carstens RP (2007) Heterogeneous ribonucleoprotein m is a splicing regulatory protein that can enhance or silence splicing of alternatively spliced exons. J Biol Chem 282:36265–36274. doi:10.1074/jbc.M704188200 Huang P-R, Hung S-C, Wang T-CV (2010) Telomeric DNA-binding activities of heterogeneous nuclear ribonucleoprotein A3 in vitro and in vivo. Biochim Biophys Acta 1803:1164–1174. doi:10.1016/j.bbamcr.2010.06.003 Hussey GS, Chaudhury A, Dawson AE et al (2011) Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. Mol Cell 41:419–431. doi:10.1016/j.molcel.2011.02.003 Hutchins EJ, Szaro BG (2013) c-Jun N-terminal kinase phosphorylation of heterogeneous nuclear ribonucleoprotein K regulates vertebrate axon outgrowth via a posttranscriptional mechanism. J Neurosci 33:14666–14680. doi:10.1523/JNEUROSCI.4821-12.2013 Jafarifar F, Yao P, Eswarappa SM, Fox PL (2011) Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L. EMBO J 30:1324–1334. doi:10.1038/emboj.2011.38 Jean-Philippe J, Paz S, Caputi M (2013) hnRNP A1: the Swiss army knife of gene expression. Int J Mol Sci 14:18999–19024. doi:10.3390/ijms140918999 Jensen KB, Dredge BK, Stefani G et al (2000) Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 25:359–371. doi:10.1016/S0896-6273(00)80900-9 Ji X, Wan J, Vishnu M et al (2013) αCP Poly(C) binding proteins act as global regulators of alternative polyadenylation. Mol Cell Biol 33:2560–2573. doi:10.1128/MCB.01380-12 Kashima T, Rao N, David CJ, Manley JL (2007) hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Hum Mol Genet 16:3149–3159. doi:10.1093/hmg/ddm276 Kiledjian M, Dreyfuss G (1992) Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J 11:2655–2664 Kim HJ, Kim NC, Wang Y-D et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473. doi:10.1038/nature11922 Ko JL, Loh HH (2001) Single-stranded DNA-binding complex involved in transcriptional regulation of mouse mu-opioid receptor gene. J Biol Chem 276:788–795. doi:10.1074/jbc.M004279200 Lagier-Tourenne C, Baughn M, Rigo F et al (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci USA 110:E4530–E4539. doi:10.1073/pnas.1318835110 Lai CP-K, Breakefield XO (2012) Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol 3:228. doi:10.3389/fphys.2012.00228 Le Ber I, Van Bortel I, Nicolas G et al (2014) hnRNPA2B1 and hnRNPA1 mutations are rare in patients with “multisystem proteinopathy” and frontotemporal lobar degeneration phenotypes. Neurobiol Aging 35(934):e5–e6. doi:10.1016/j.neurobiolaging.2013.09.016 Lee EK, Kim HH, Kuwano Y et al (2010) hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nat Struct Mol Biol 17:732–739. doi:10.1038/nsmb.1815 Lee Y-B, Chen H-J, Peres JN et al (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep 5:1178–1186. doi:10.1016/j.celrep.2013.10.049 Lee H-R, Kim T-D, Kim H-J et al (2015) Heterogeneous ribonucleoprotein R regulates arylalkylamine N-acetyltransferase synthesis via internal ribosomal entry site-mediated translation in a circadian manner. J Pineal Res 59:518–529. doi:10.1111/jpi.12284 Leffers H, Dejgaard K, Celis JE (1995) Characterisation of two major cellular poly(rC)-binding human proteins, each containing three K-homologous (KH) domains. Eur J Biochem 230:447–453. doi:10.1111/j.1432-1033.1995.tb20581.x Li H, Guo L, Huang A et al (2015) Nanoparticle-conjugated aptamer targeting hnRNP A2/B1 can recognize multiple tumor cells and inhibit their proliferation. Biomaterials 63:168–176. doi:10.1016/j.biomaterials.2015.06.013 Lian W-X, Yin R-H, Kong X-Z et al (2012) THAP11, a novel binding protein of PCBP1, negatively regulates CD44 alternative splicing and cell invasion in a human hepatoma cell line. FEBS Lett 586:1431–1438. doi:10.1016/j.febslet.2012.04.016 Liu Y, Szaro BG (2011) hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis. Development 138:3079–3090. doi:10.1242/dev.066993 Liu Y, Gervasi C, Szaro BG (2008) A crucial role for hnRNP K in axon development in Xenopus laevis. Development 135:3125–3135. doi:10.1242/dev.022236 Liu Y, Bourgeois CF, Pang S et al (2009) The germ cell nuclear proteins hnRNP G-T and RBMY activate a testis-specific exon. PLoS Genet 5:e1000707. doi:10.1371/journal.pgen.1000707 Liu X, Zhou Y, Lou Y, Zhong H (2015) Knockdown of HNRNPA1 inhibits lung adenocarcinoma cell proliferation through cell cycle arrest at G0/G1 phase. Gene 576:791–797. doi:10.1016/j.gene.2015.11.009 Llères D, Denegri M, Biggiogera M et al (2010) Direct interaction between hnRNP-M and CDC5L/PLRG1 proteins affects alternative splice site choice. EMBO Rep 11:445–451. doi:10.1038/embor.2010.64 Loh TJ, Moon H, Cho S et al (2015) CD44 alternative splicing and hnRNP A1 expression are associated with the metastasis of breast cancer. Oncol Rep 34:1231–1238. doi:10.3892/or.2015.4110 Majumder M, Yaman I, Gaccioli F et al (2009) The hnRNA-binding proteins hnRNP L and PTB are required for efficient translation of the Cat-1 arginine/lysine transporter mRNA during amino acid starvation. Mol Cell Biol 29:2899–2912. doi:10.1128/MCB.01774-08 Makeyev AV, Liebhaber SA (2002) The poly(C)-binding proteins: a multiplicity of functions and a search for mechanisms. RNA 8:265–278. doi:10.1017/S1355838202024627 Malik AK, Flock KE, Godavarthi CL et al (2006) Molecular basis underlying the poly C binding protein 1 as a regulator of the proximal promoter of mouse mu-opioid receptor gene. Brain Res 1112:33–45. doi:10.1016/j.brainres.2006.07.019 Marko M, Leichter M, Patrinou-Georgoula M, Guialis A (2010) hnRNP M interacts with PSF and p54(nrb) and co-localizes within defined nuclear structures. Exp Cell Res 316:390–400. doi:10.1016/j.yexcr.2009.10.021 Mayeda A, Krainer AR (1992) Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell 68:365–375 McCloskey A, Taniguchi I, Shinmyozu K, Ohno M (2012) hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science 335:1643–1646. doi:10.1126/science.1218469 Melton AA, Jackson J, Wang J, Lynch KW (2007) Combinatorial control of signal-induced exon repression by hnRNP L and PSF. Mol Cell Biol 27:6972–6984. doi:10.1128/MCB.00419-07 Meng Q, Rayala SK, Gururaj AE et al (2007) Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1. Proc Natl Acad Sci USA 104:5866–5871. doi:10.1073/pnas.0701065104 Mohagheghi F, Prudencio M, Stuani C et al (2015) TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor. Hum Mol Genet. doi:10.1093/hmg/ddv491 Mori K, Lammich S, Mackenzie IRA et al (2013) hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol 125:413–423. doi:10.1007/s00401-013-1088-7 Motta-Mena LB, Heyd F, Lynch KW (2010) Context-dependent regulatory mechanism of the splicing factor hnRNP L. Mol Cell 37:223–234. doi:10.1016/j.molcel.2009.12.027 Mourelatos Z, Abel L, Yong J et al (2001) SMN interacts with a novel family of hnRNP and spliceosomal proteins. EMBO J 20:5443–5452. doi:10.1093/emboj/20.19.5443 Moursy A, Allain FH-T, Cléry A (2014) Characterization of the RNA recognition mode of hnRNP G extends its role in SMN2 splicing regulation. Nucleic Acids Res 42:6659–6672. doi:10.1093/nar/gku244 Muslimov IA, Tuzhilin A, Tang TH et al (2014) Interactions of noncanonical motifs with hnRNP A2 promote activity-dependent RNA transport in neurons. J Cell Biol 205:493–510. doi:10.1083/jcb.201310045 Naarmann IS, Harnisch C, Flach N et al (2008) mRNA silencing in human erythroid cell maturation: heterogeneous nuclear ribonucleoprotein K controls the expression of its regulator c-Src. J Biol Chem 283:18461–18472. doi:10.1074/jbc.M710328200 Oren M, Rotter V (2010) Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol 2:a001107. doi:10.1101/cshperspect.a001107 Ostareck DH, Ostareck-Lederer A, Wilm M et al (1997) mRNA silencing in erythroid differentiation: hnRNP K and hnRNP E1 regulate 15-lipoxygenase translation from the 3′ end. Cell 89:597–606. doi:10.1016/S0092-8674(00)80241-X Park E, Iaccarino C, Lee J et al (2011) Regulatory roles of heterogeneous nuclear ribonucleoprotein M and Nova-1 protein in alternative splicing of dopamine D2 receptor pre-mRNA. J Biol Chem 286:25301–25308. doi:10.1074/jbc.M110.206540 Park SJ, Lee H, Jo DS et al (2015) Heterogeneous nuclear ribonucleoprotein A1 post-transcriptionally regulates Drp1 expression in neuroblastoma cells. Biochim Biophys Acta 1849:1423–1431. doi:10.1016/j.bbagrm.2015.10.017 Patton JG, Mayer SA, Tempst P, Nadal-Ginard B (1991) Characterization and molecular cloning of polypyrimidine tract-binding protein: a component of a complex necessary for pre-mRNA splicing. Genes Dev 5:1237–1251 Pickering BM, Mitchell SA, Evans JR, Willis AE (2003) Polypyrimidine tract binding protein and poly r(C) binding protein 1 interact with the BAG-1 IRES and stimulate its activity in vitro and in vivo. Nucleic Acids Res 31:639–646. doi:10.1093/nar/gkg146 Pont AR, Sadri N, Hsiao SJ et al (2012) mRNA decay factor AUF1 maintains normal aging, telomere maintenance, and suppression of senescence by activation of telomerase transcription. Mol Cell 47:5–15. doi:10.1016/j.molcel.2012.04.019 Porensky PN, Burghes AHM (2013) Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther 24:489–498. doi:10.1089/hum.2012.225 Qu X-H, Liu J-L, Zhong X-W et al (2015) Insights into the roles of hnRNP A2/B1 and AXL in non-small cell lung cancer. Oncol Lett 10:1677–1685. doi:10.3892/ol.2015.3457 Rahman MA, Masuda A, Ohe K et al (2013) HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. Sci Rep 3:2931. doi:10.1038/srep02931 Ren C, Cho S-J, Jung Y-S, Chen X (2014) DNA polymerase η is regulated by poly(rC)-binding protein 1 via mRNA stability. Biochem J 464:377–386. doi:10.1042/BJ20141164 Riboldi G, Zanetta C, Ranieri M et al (2014) Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases. Mol Neurobiol 50:721–732. doi:10.1007/s12035-014-8724-7 Rossbach O, Hung L-H, Khrameeva E et al (2014) Crosslinking-immunoprecipitation (iCLIP) analysis reveals global regulatory roles of hnRNP L. RNA Biol 11:146–155. doi:10.4161/rna.27991 Samatanga B, Dominguez C, Jelesarov I, Allain FH-T (2013) The high kinetic stability of a G-quadruplex limits hnRNP F qRRM3 binding to G-tract RNA. Nucleic Acids Res 41:2505–2516. doi:10.1093/nar/gks1289 Shan J, Moran-Jones K, Munro TP et al (2000) Binding of an RNA trafficking response element to heterogeneous nuclear ribonucleoproteins A1 and A2. J Biol Chem 275:38286–38295. doi:10.1074/jbc.M007642200 Shan J, Munro TP, Barbarese E et al (2003) A molecular mechanism for mRNA trafficking in neuronal dendrites. J Neurosci 23:8859–8866 Sharma S, Falick AM, Black DL (2005) Polypyrimidine tract binding protein blocks the 5′ splice site-dependent assembly of U2AF and the prespliceosomal E complex. Mol Cell 19:485–496. doi:10.1016/j.molcel.2005.07.014 Siomi H, Matunis MJ, Michael WM, Dreyfuss G (1993) The pre-mRNA binding K protein contains a novel evolutionarily conserved motif. Nucleic Acids Res 21:1193–1198 Söderberg M, Raffalli-Mathieu F, Lang MA (2007) Identification of a regulatory cis-element within the 3′-untranslated region of the murine inducible nitric oxide synthase (iNOS) mRNA; interaction with heterogeneous nuclear ribonucleoproteins I and L and role in the iNOS gene expression. Mol Immunol 44:434–442. doi:10.1016/j.molimm.2006.02.019 Soulard M, Della Valle V, Siomi MC et al (1993) hnRNP G: sequence and characterization of a glycosylated RNA-binding protein. Nucleic Acids Res 21:4210–4217 Stains JP, Lecanda F, Towler DA, Civitelli R (2005) Heterogeneous nuclear ribonucleoprotein K represses transcription from a cytosine/thymidine-rich element in the osteocalcin promoter. Biochem J 385:613–623. doi:10.1042/BJ20040680 Svitkin YV, Yanagiya A, Karetnikov AE et al (2013) Control of translation and miRNA-dependent repression by a novel poly(A) binding protein, hnRNP-Q. PLoS Biol 11:e1001564. doi:10.1371/journal.pbio.1001564 Swanson MS, Nakagawa TY, LeVan K, Dreyfuss G (1987) Primary structure of human nuclear ribonucleoprotein particle C proteins: conservation of sequence and domain structures in heterogeneous nuclear RNA, mRNA, and pre-rRNA-binding proteins. Mol Cell Biol 7:1731–1739 Théry C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579. doi:10.1038/nri855 Thyagarajan A, Szaro BG (2004) Phylogenetically conserved binding of specific K homology domain proteins to the 3′-untranslated region of the vertebrate middle neurofilament mRNA. J Biol Chem 279:49680–49688. doi:10.1074/jbc.M408915200 Thyagarajan A, Szaro BG (2008) Dynamic endogenous association of neurofilament mRNAs with K-homology domain ribonucleoproteins in developing cerebral cortex. Brain Res 1189:33–42. doi:10.1016/j.brainres.2007.11.012 Tietje A, Maron KN, Wei Y, Feliciano DM (2014) Cerebrospinal fluid extracellular vesicles undergo age dependent declines and contain known and novel non-coding RNAs. PLoS One 9:e113116. doi:10.1371/journal.pone.0113116 Tsuiji H, Iguchi Y, Furuya A et al (2013) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med 5:221–234. doi:10.1002/emmm.201202303 van Eekelen CA, Riemen T, van Venrooij WJ (1981) Specificity in the interaction of hnRNA and mRNA with proteins as revealed by in vivo cross linking. FEBS Lett 130:223–226 Vance C, Rogelj B, Hortobágyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211. doi:10.1126/science.1165942 Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F et al (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980. doi:10.1038/ncomms3980 Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C et al (2014) Sorting it out: regulation of exosome loading. Semin Cancer Biol 28:3–13. doi:10.1016/j.semcancer.2014.04.009 Vu NT, Park MA, Shultz JC et al (2013) hnRNP U enhances caspase-9 splicing and is modulated by AKT-dependent phosphorylation of hnRNP L. J Biol Chem 288:8575–8584. doi:10.1074/jbc.M112.443333 Waggoner SA, Johannes GJ, Liebhaber SA (2009) Depletion of the poly(C)-binding proteins αCP1 and αCP2 from K562 cells leads to p53-independent induction of cyclin-dependent kinase inhibitor (CDKN1A) and G1 arrest. J Biol Chem 284:9039–9049. doi:10.1074/jbc.M806986200 Waibel S, Neumann M, Rabe M et al (2010) Novel missense and truncating mutations in FUS/TLS in familial ALS. Neurology 75:815–817. doi:10.1212/WNL.0b013e3181f07e26 Wang Y, Wang J, Gao L et al (2011) An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5′ splice site of tau exon 10, whose misregulation causes frontotemporal dementia. Gene 485:130–138. doi:10.1016/j.gene.2011.06.020 Williams KR, McAninch DS, Stefanovic S et al (2015) hnRNP-Q1 represses nascent axon growth in cortical neurons by inhibiting gap-43 mRNA translation. Mol Biol Cell. doi:10.1091/mbc.E15-07-0504 Wu H, Henras A, Chanfreau G, Feigon J (2004) Structural basis for recognition of the AGNN tetraloop RNA fold by the double-stranded RNA-binding domain of Rnt1p RNase III. Proc Natl Acad Sci USA 101:8307–8312. doi:10.1073/pnas.0402627101 Xing L, Yao X, Williams KR, Bassell GJ (2012) Negative regulation of RhoA translation and signaling by hnRNP-Q1 affects cellular morphogenesis. Mol Biol Cell 23:1500–1509. doi:10.1091/mbc.E11-10-0867 Xu Y, Gao XD, Lee J-H et al (2014) Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing. Genes Dev 28:1191–1203. doi:10.1101/gad.241968.114 Yoon Y, McKenna MC, Rollins DA et al (2013) Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK. Proc Natl Acad Sci 110:11624–11629. doi:10.1073/pnas.1301485110 Zhang T, Huang X-H, Dong L et al (2010) PCBP-1 regulates alternative splicing of the CD44 gene and inhibits invasion in human hepatoma cell line HepG2 cells. Mol Cancer 9:72. doi:10.1186/1476-4598-9-72 Zhang C, Lee K-Y, Swanson MS, Darnell RB (2013a) Prediction of clustered RNA-binding protein motif sites in the mammalian genome. Nucleic Acids Res 41:6793–6807. doi:10.1093/nar/gkt421 Zhang W, Zeng F, Liu Y et al (2013b) Crystal structures and RNA-binding properties of the RNA recognition motifs of heterogeneous nuclear ribonucleoprotein L: insights into its roles in alternative splicing regulation. J Biol Chem 288:22636–22649. doi:10.1074/jbc.M113.463901