Historical Background
As nascent messenger RNA (mRNA) is transcribed, it becomes associated with a variety of proteins, collectively termed heterogeneous nuclear ribonucleoproteins (hnRNPs) that will accompany the mRNA transcript through its lifecycle. HnRNPs play critical roles in all aspects of mRNA metabolism and function. From the regulation of transcription to splicing, transport, localization, and stability, these proteins are essential for proper regulation of gene expression. HnRNP A1, a member of the hnRNP A/B family, is one of the best studied hnRNPs (Bekenstein and Soreq 2013; Jean-Philippe et al. 2013). Here, we review the structure and diverse molecular functions of hnRNP A1, with particular emphasis on its involvement in human diseases.
Historically, the presence of cytoplasmic granules and fibrils in basophilic cells has been initially demonstrated using electron microscopy studies (Porter 1954;...
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References
Barraud P, Allain FH. Solution structure of the two RNA recognition motifs of hnRNP A1 using segmental isotope labeling: how the relative orientation between RRMs influences the nucleic acid binding topology. J Biomol NMR. 2013;55:119–38. https://doi.org/10.1007/s10858-012-9696-4.
Bekenstein U, Soreq H. Heterogeneous nuclear ribonucleoprotein A1 in health and neurodegenerative disease: from structural insights to post-transcriptional regulatory roles. Mol Cell Neurosci. 2013;56:436–46. https://doi.org/10.1016/j.mcn.2012.12.002.
Berson A, Barbash S, Shaltiel G, Goll Y, Hanin G, Greenberg DS, et al. Cholinergic-associated loss of hnRNP-A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice. EMBO Mol Med. 2012;4:730–42. https://doi.org/10.1002/emmm.201100995.
Beyer AL, Christensen ME, Walker BW, LeStourgeon WM. Identification and characterization of the packaging proteins of core 40S hnRNP particles. Cell. 1977;11:127–38.
Biamonti G, Bassi MT, Cartegni L, Mechta F, Buvoli M, Cobianchi F, et al. Human hnRNP protein A1 gene expression. Structural and functional characterization of the promoter. J Mol Biol. 1993;230:77–89. https://doi.org/10.1006/jmbi.1993.1127.
Blanchette M, Chabot B. Modulation of exon skipping by high-affinity hnRNP A1-binding sites and by intron elements that repress splice site utilization. EMBO J. 1999;18:1939–52. https://doi.org/10.1093/emboj/18.7.1939.
Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala YM, Baralle FE. TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J Biol Chem. 2005;280:37572–84. https://doi.org/10.1074/jbc.M505557200.
Burd CG, Dreyfuss G. RNA binding specificity of hnRNP A1: significance of hnRNP A1 high-affinity binding sites in pre-mRNA splicing. EMBO J. 1994;13:1197–204.
Buvoli M, Cobianchi F, Riva S. Interaction of hnRNP A1 with snRNPs and pre-mRNAs: evidence for a possible role of A1 RNA annealing activity in the first steps of spliceosome assembly. Nucleic Acids Res. 1992;20:5017–25.
Calini D, Corrado L, Del Bo R, Gagliardi S, Pensato V, Verde F, et al. Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2013;34:2695.e11–2. https://doi.org/10.1016/j.neurobiolaging.2013.05.025.
Campillos M, Lamas JR, Garcia MA, Bullido MJ, Valdivieso F, Vazquez J. Specific interaction of heterogeneous nuclear ribonucleoprotein A1 with the -219 T allelic form modulates APOE promoter activity. Nucleic Acids Res. 2003;31:3063–70.
Cartegni L, Maconi M, Morandi E, Cobianchi F, Riva S, Biamonti G. hnRNP A1 selectively interacts through its Gly-rich domain with different RNA-binding proteins. J Mol Biol. 1996;259:337–48. https://doi.org/10.1006/jmbi.1996.0324.
Chen H, Hewison M, Hu B, Adams JS. Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance. Proc Natl Acad Sci U S A. 2003;100:6109–14. https://doi.org/10.1073/pnas.1031395100.
Cheunim T, Zhang J, Milligan SG, McPhillips MG, Graham SV. The alternative splicing factor hnRNP A1 is up-regulated during virus-infected epithelial cell differentiation and binds the human papillomavirus type 16 late regulatory element. Virus Res. 2008;131:189–98. https://doi.org/10.1016/j.virusres.2007.09.006.
Choi YH, Lim JK, Jeong MW, Kim KT. HnRNP A1 phosphorylated by VRK1 stimulates telomerase and its binding to telomeric DNA sequence. Nucleic Acids Res. 2012;40:8499–518. https://doi.org/10.1093/nar/gks634.
Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, et al. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 2015;130:63–75. https://doi.org/10.1007/s00401-015-1429-9.
Dallaire F, Dupuis S, Fiset S, Chabot B. Heterogeneous nuclear ribonucleoprotein A1 and UP1 protect mammalian telomeric repeats and modulate telomere replication in vitro. J Biol Chem. 2000;275:14509–16.
David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463:364–8. https://doi.org/10.1038/nature08697.
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–56. https://doi.org/10.1016/j.neuron.2011.09.011.
Ding J, Hayashi MK, Zhang Y, Manche L, Krainer AR, Xu RM. Crystal structure of the two-RRM domain of hnRNP A1 (UP1) complexed with single-stranded telomeric DNA. Genes Dev. 1999;13:1102–15.
Donev R, Newall A, Thome J, Sheer D. A role for SC35 and hnRNPA1 in the determination of amyloid precursor protein isoforms. Mol Psychiatry. 2007;12:681–90. https://doi.org/10.1038/sj.mp.4001971.
Douglas JN, Gardner LA, Salapa HE, Lalor SJ, Lee S, Segal BM, et al. Antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in a model of central nervous system autoimmune inflammatory disease. J Neuroinflammation. 2016;13:178. https://doi.org/10.1186/s12974-016-0647-y.
Dreyfuss G, Matunis MJ, Pinol-Roma S, Burd CG. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321. https://doi.org/10.1146/annurev.bi.62.070193.001445.
Enokizono Y, Matsugami A, Uesugi S, Fukuda H, Tsuchiya N, Sugimura T, et al. Destruction of quadruplex by proteins, and its biological implications in replication and telomere maintenance. Nucleic Acids Res Suppl. 2003;62:231–2.
Fay J, Kelehan P, Lambkin H, Schwartz S. Increased expression of cellular RNA-binding proteins in HPV-induced neoplasia and cervical cancer. J Med Virol. 2009;81:897–907. https://doi.org/10.1002/jmv.21406.
Fiset S, Chabot B. hnRNP A1 may interact simultaneously with telomeric DNA and the human telomerase RNA in vitro. Nucleic Acids Res. 2001;29:2268–75.
Fisette JF, Toutant J, Dugre-Brisson S, Desgroseillers L, Chabot B. hnRNP A1 and hnRNP H can collaborate to modulate 5' splice site selection. RNA. 2010;16:228–38. https://doi.org/10.1261/rna.1890310.
Flynn RL, Centore RC, O'Sullivan RJ, Rai R, Tse A, Songyang Z, et al. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature. 2011;471:532–6. https://doi.org/10.1038/nature09772.
Gall JG. Small granules in the amphibian oocyte nucleus and their relationship to RNA. J Biophys Biochem Cytol. 1956;2:393–6.
Guil S, Caceres JF. The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol. 2007;14:591–6. https://doi.org/10.1038/nsmb1250.
Hudson JS, Ding L, Le V, Lewis E, Graves D. Recognition and binding of human telomeric G-quadruplex DNA by unfolding protein 1. Biochemistry. 2014;53:3347–56. https://doi.org/10.1021/bi500351u.
Iervolino A, Santilli G, Trotta R, Guerzoni C, Cesi V, Bergamaschi A, et al. hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. Mol Cell Biol. 2002;22:2255–66.
Izumi R, Warita H, Niihori T, Takahashi T, Tateyama M, Suzuki N, et al. Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation. Neurol Genet. 2015;1:e23. https://doi.org/10.1212/NXG.0000000000000023.
Jean-Philippe J, Paz S, Caputi M. hnRNP A1: the Swiss army knife of gene expression. Int J Mol Sci. 2013;14:18999–9024. https://doi.org/10.3390/ijms140918999.
Kiledjian M, Dreyfuss G. Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J. 1992;11:2655–64.
Kim S, Merrill BM, Rajpurohit R, Kumar A, Stone KL, Papov VV, et al. Identification of N(G)-methylarginine residues in human heterogeneous RNP protein A1: Phe/Gly-Gly-Gly-Arg-Gly-Gly-Gly/Phe is a preferred recognition motif. Biochemistry. 1997;36:5185–92. https://doi.org/10.1021/bi9625509.
Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467–73. https://doi.org/10.1038/nature11922.
LaBranche H, Dupuis S, Ben-David Y, Bani MR, Wellinger RJ, Chabot B. Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nat Genet. 1998;19:199–202. https://doi.org/10.1038/575.
Lau JS, Baumeister P, Kim E, Roy B, Hsieh TY, Lai M, et al. Heterogeneous nuclear ribonucleoproteins as regulators of gene expression through interactions with the human thymidine kinase promoter. J Cell Biochem. 2000;79:395–406.
Le Ber I, Van Bortel I, Nicolas G, Bouya-Ahmed K, Camuzat A, Wallon D, et al. hnRNPA2B1 and hnRNPA1 mutations are rare in patients with "multisystem proteinopathy" and frontotemporal lobar degeneration phenotypes. Neurobiol Aging. 2014;35:934 e5–6. https://doi.org/10.1016/j.neurobiolaging.2013.09.016.
Levin MC, Lee SM, Kalume F, Morcos Y, Dohan Jr FC, Hasty KA, et al. Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med. 2002;8:509–13. https://doi.org/10.1038/nm0502-509.
Li HF, Wu ZY. Genotype-phenotype correlations of amyotrophic lateral sclerosis. Transl Neurodegener. 2016;5:3. https://doi.org/10.1186/s40035-016-0050-8.
Mayeda A, Krainer AR. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell. 1992;68:365–75.
Mayeda A, Munroe SH, Caceres JF, Krainer AR. Function of conserved domains of hnRNP A1 and other hnRNP A/B proteins. EMBO J. 1994;13:5483–95.
Mayeda A, Munroe SH, Xu RM, Krainer AR. Distinct functions of the closely related tandem RNA-recognition motifs of hnRNP A1. RNA. 1998;4:1111–23.
Michael WM, Choi M, Dreyfuss G. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell. 1995;83:415–22.
Michlewski G, Caceres JF. Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nat Struct Mol Biol. 2010;17:1011–8. https://doi.org/10.1038/nsmb.1874.
Nadler SG, Merrill BM, Roberts WJ, Keating KM, Lisbin MJ, Barnett SF, et al. Interactions of the A1 heterogeneous nuclear ribonucleoprotein and its proteolytic derivative, UP1, with RNA and DNA: evidence for multiple RNA binding domains and salt-dependent binding mode transitions. Biochemistry. 1991;30:2968–76.
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–3. https://doi.org/10.1126/science.1134108.
Palade GE. A small particulate component of the cytoplasm. J Biophys Biochem Cytol. 1955;1:59–68.
Pino I, Pio R, Toledo G, Zabalegui N, Vicent S, Rey N, et al. Altered patterns of expression of members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family in lung cancer. Lung Cancer. 2003;41:131–43.
Pinol-Roma S, Choi YD, Matunis MJ, Dreyfuss G. Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins. Genes Dev. 1988;2:215–27.
Pollard VW, Michael WM, Nakielny S, Siomi MC, Wang F, Dreyfuss G. A novel receptor-mediated nuclear protein import pathway. Cell. 1996;86:985–94.
Porter KR. Electron microscopy of basophilic components of cytoplasm. J Histochem Cytochem. 1954;2:346–75.
Rajpurohit R, Paik WK, Kim S. Effect of enzymic methylation of heterogeneous ribonucleoprotein particle A1 on its nucleic-acid binding and controlled proteolysis. Biochem J. 1994;304(Pt 3):903–9.
Rebane A, Aab A, Steitz JA. Transportins 1 and 2 are redundant nuclear import factors for hnRNP A1 and HuR. RNA. 2004;10:590–9.
Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–68. https://doi.org/10.1016/j.neuron.2011.09.010.
Samarina OP, Lukanidin EM, Molnar J, Georgiev GP. Structural organization of nuclear complexes containing DNA-like RNA. J Mol Biol. 1968;33:251–63.
Sengupta S, Lakhotia SC. Altered expressions of the noncoding hsromega gene enhances poly-Q-induced neurotoxicity in Drosophila. RNA Biol. 2006;3:28–35.
Shi Y, Frost PJ, Hoang BQ, Benavides A, Sharma S, Gera JF, et al. IL-6-induced stimulation of c-myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. Cancer Res. 2008;68:10215–22. https://doi.org/10.1158/0008-5472.CAN-08-1066.
Siomi H, Dreyfuss G. A nuclear localization domain in the hnRNP A1 protein. J Cell Biol. 1995;129:551–60.
Siomi MC, Eder PS, Kataoka N, Wan L, Liu Q, Dreyfuss G. Transportin-mediated nuclear import of heterogeneous nuclear RNP proteins. J Cell Biol. 1997;138:1181–92.
Sjostrand FS, Hanzon V. Membrane structures of cytoplasm and mitochondria in exocrine cells of mouse pancreas as revealed by high resolution electron microscopy. Exp Cell Res. 1954;7:393–414.
Swanson MS, Dreyfuss G. RNA binding specificity of hnRNP proteins: a subset bind to the 3' end of introns. EMBO J. 1988;7:3519–29.
Tavanez JP, Madl T, Kooshapur H, Sattler M, Valcarcel J. hnRNP A1 proofreads 3' splice site recognition by U2AF. Mol Cell. 2012;45:314–29. https://doi.org/10.1016/j.molcel.2011.11.033.
Ting NS, Pohorelic B, Yu Y, Lees-Miller SP, Beattie TL. The human telomerase RNA component, hTR, activates the DNA-dependent protein kinase to phosphorylate heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res. 2009;37:6105–15. https://doi.org/10.1093/nar/gkp636.
Ushigome M, Ubagai T, Fukuda H, Tsuchiya N, Sugimura T, Takatsuka J, et al. Up-regulation of hnRNP A1 gene in sporadic human colorectal cancers. Int J Oncol. 2005;26:635–40.
van Eekelen CA, Riemen T, van Venrooij WJ. Specificity in the interaction of hnRNA and mRNA with proteins as revealed by in vivo cross linking. FEBS Lett. 1981;130:223–6.
Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, Perez-Hernandez D, Vazquez J, Martin-Cofreces N, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980. https://doi.org/10.1038/ncomms3980.
Vitali J, Ding J, Jiang J, Zhang Y, Krainer AR, Xu RM. Correlated alternative side chain conformations in the RNA-recognition motif of heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res. 2002;30:1531–8.
Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic RNP machine. Cell. 2009;136:701–18. https://doi.org/10.1016/j.cell.2009.02.009.
Xia H. Regulation of gamma-fibrinogen chain expression by heterogeneous nuclear ribonucleoprotein A1. J Biol Chem. 2005;280:13171–8. https://doi.org/10.1074/jbc.M414120200.
Yu C, Guo J, Liu Y, Jia J, Jia R, Fan M. Oral squamous cancer cell exploits hnRNP A1 to regulate cell cycle and proliferation. J Cell Physiol. 2015;230:2252–61. https://doi.org/10.1002/jcp.24956.
Zhang QS, Manche L, Xu RM, Krainer AR. hnRNP A1 associates with telomere ends and stimulates telomerase activity. RNA. 2006;12:1116–28. https://doi.org/10.1261/rna.58806.
Zhou ZJ, Dai Z, Zhou SL, Fu XT, Zhao YM, Shi YH, et al. Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. Int J Cancer. 2013;132:1080–9. https://doi.org/10.1002/ijc.27742.
Acknowledgments
The authors are grateful to all of our group members who contributed to the interest in hnRNP A1 and to the work involved. This study was supported by the Israeli Ministry of Science Aging program (to H.S) and by the NIH (F32-NS084667 to A.B.). We apologize to any colleagues whose work could not be covered due to space limitations.
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Berson, A., Soreq, H. (2018). HNRNPA1. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101642
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