HNRNPA2B1 explained

Heterogeneous nuclear ribonucleoproteins A2/B1 is a protein that in humans is encoded by the HNRNPA2B1 gene.^[1]

Structure

HNRNPA2B1 gene contains 12 exons, including a B1 protein specific 36-nucleotide mini-exon. The entire length of intron/exon organization of HNRNPA2B1 is identical to that of the HNRNPA1 gene which indicates a common origin by gene duplication.^[2]

Function

This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms.^[3] HnRNPA2B1 is an autoantigen in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and mixed connective tissue disease. When referred to as an autoantigen, hnRNPA2B1 is also known as RA33.

The HNRNPA2 and HNRNPB1 proteins are involved in packaging nascent mRNA, in alternative splicing, and in cytoplasmic RNA trafficking, translation, and stabilization. HNRNPA2 and HNRNPB1 also appear to function in telomere maintenance, cell proliferation and differentiation, and glucose transport.^{[4] [5]}

Function of HNRNPA2B1 gene can be effectively examined by siRNA knockdown based on an independent validation.^[6]

Interactions

HNRPA2B1 has been shown to interact with casein kinase 2, alpha 1.^[7]

Role in diseases

The mutation p.D290V/302V in hnRNPA2B1 is implicated in dementia, myopathy, Paget's disease of bone, and ALS.^[8] Mutations in hnRNPA2B1 and hnRNPA1 cause of amyotrophic lateral sclerosis and multisystem proteinopathy.^[9] hnRNPA2/B1 is found to activate cyclooxygenase-2 and promote tumor growth in human lung cancers.^[10]

Further reading

• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . J. Infect. . 24 . 3 . 317–20 . 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Bauw G, Rasmussen HH, van den Bulcke M, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J . Two-dimensional gel electrophoresis, protein electroblotting and microsequencing: a direct link between proteins and genes . Electrophoresis . 11 . 7 . 528–36 . 1990 . 1699755 . 10.1002/elps.1150110703 . 24768114 .
• Wilk HE, Schaefer KP, Agris PF, Boak AM, Kovacs SA . U1 SnRNP association with HnRNP involves an initial non-specific splice-site independent interaction of U1 SnRNP protein with HnRNA . Mol. Cell. Biochem. . 106 . 1 . 55–66 . 1991 . 1833625 . 10.1007/BF00231189 . 22696966 .
• Burd CG, Swanson MS, Görlach M, Dreyfuss G . Primary structures of the heterogeneous nuclear ribonucleoprotein A2, B1, and C2 proteins: a diversity of RNA binding proteins is generated by small peptide inserts . Proc. Natl. Acad. Sci. U.S.A. . 86 . 24 . 9788–92 . 1989 . 2557628 . 298587 . 10.1073/pnas.86.24.9788 . 1989PNAS...86.9788B . free .
• Kumar A, Williams KR, Szer W . Purification and domain structure of core hnRNP proteins A1 and A2 and their relationship to single-stranded DNA-binding proteins . J. Biol. Chem. . 261 . 24 . 11266–73 . 1986 . 10.1016/S0021-9258(18)67378-8 . 3733753 . free .
• Faura M, Renau-Piqueras J, Bachs O, Bosser R . Differential distribution of heterogeneous nuclear ribonucleoproteins in rat tissues . Biochem. Biophys. Res. Commun. . 217 . 2 . 554–60 . 1995 . 7503735 . 10.1006/bbrc.1995.2811 .
• Kozu T, Henrich B, Schäfer KP . Structure and expression of the gene (HNRPA2B1) encoding the human hnRNP protein A2/B1 . Genomics . 25 . 2 . 365–71 . 1995 . 7789969 . 10.1016/0888-7543(95)80035-K .
• Van Laer L, Van Camp G, Green ED, Huizing EH, Willems PJ . Physical mapping of the HOXA1 gene and the hnRPA2B1 gene in a YAC contig from human chromosome 7p14-p15 . Hum. Genet. . 99 . 6 . 831–3 . 1997 . 9187682 . 10.1007/s004390050457 . 42177403 .
• Neubauer G, King A, Rappsilber J, Calvio C, Watson M, Ajuh P, Sleeman J, Lamond A, Mann M . Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex . Nat. Genet. . 20 . 1 . 46–50 . 1998 . 9731529 . 10.1038/1700 . 585778 .
• Montuenga LM, Zhou J, Avis I, Vos M, Martinez A, Cuttitta F, Treston AM, Sunday M, Mulshine JL . Expression of heterogeneous nuclear ribonucleoprotein A2/B1 changes with critical stages of mammalian lung development . Am. J. Respir. Cell Mol. Biol. . 19 . 4 . 554–62 . 1998 . 9761751 . 10.1165/ajrcmb.19.4.3185 . 10171/20162 . free .
• Pancetti F, Bosser R, Krehan A, Pyerin W, Itarte E, Bachs O . Heterogeneous nuclear ribonucleoprotein A2 interacts with protein kinase CK2 . Biochem. Biophys. Res. Commun. . 260 . 1 . 17–22 . 1999 . 10381337 . 10.1006/bbrc.1999.0849 .
• Hamilton BJ, Nichols RC, Tsukamoto H, Boado RJ, Pardridge WM, Rigby WF . hnRNP A2 and hnRNP L bind the 3'UTR of glucose transporter 1 mRNA and exist as a complex in vivo . Biochem. Biophys. Res. Commun. . 261 . 3 . 646–51 . 1999 . 10441480 . 10.1006/bbrc.1999.1040 . free .
• Nichols RC, Wang XW, Tang J, Hamilton BJ, High FA, Herschman HR, Rigby WF . The RGG domain in hnRNP A2 affects subcellular localization . Exp. Cell Res. . 256 . 2 . 522–32 . 2000 . 10772824 . 10.1006/excr.2000.4827 .
• Matsui M, Horiguchi H, Kamma H, Fujiwara M, Ohtsubo R, Ogata T . Testis- and developmental stage-specific expression of hnRNP A2/B1 splicing isoforms, B0a/b . Biochim. Biophys. Acta . 1493 . 1–2 . 33–40 . 2000 . 10978504 . 10.1016/s0167-4781(00)00154-8 .
• Zhou J, Allred DC, Avis I, Martínez A, Vos MD, Smith L, Treston AM, Mulshine JL . Differential expression of the early lung cancer detection marker, heterogeneous nuclear ribonucleoprotein-A2/B1 (hnRNP-A2/B1) in normal breast and neoplastic breast cancer . Breast Cancer Res. Treat. . 66 . 3 . 217–24 . 2001 . 11510693 . 10.1023/A:1010631915831 . 27708432 .
• Pioli PA, Rigby WF . The von Hippel-Lindau protein interacts with heteronuclear ribonucleoprotein a2 and regulates its expression . J. Biol. Chem. . 276 . 43 . 40346–52 . 2001 . 11517223 . 10.1074/jbc.M105391200 . free .
• Book: Kim SH, Dierssen M, Ferreres JC, Fountoulakis M, Lubec G . Journal of Neural Transmission. Supplementum . Protein Expression in Down Syndrome Brain . Increased protein levels of heterogeneous nuclear ribonucleoprotein A2/B1 in fetal Down syndrome brains . 61 . 273–80 . 2001 . 11771750 . 10.1007/978-3-7091-6262-0_22 . 978-3-211-83704-7 .
• Andersen JS, Lyon CE, Fox AH, Leung AK, Lam YW, Steen H, Mann M, Lamond AI . Directed proteomic analysis of the human nucleolus . Curr. Biol. . 12 . 1 . 1–11 . 2002 . 11790298 . 10.1016/S0960-9822(01)00650-9 . 14132033 . free . 2002CBio...12....1A .
• Jurica MS, Licklider LJ, Gygi SR, Grigorieff N, Moore MJ . Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis . RNA . 8 . 4 . 426–39 . 2002 . 11991638 . 1370266 . 10.1017/S1355838202021088 .
• Li S, Zhang P, Freibaum BD, et al.. Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy . Human Molecular Genetics . 25 . 5 . 936–950 . 2016 . 26744327 . 10.1093/hmg/ddv627 . 4754048.
• Herman S, Fischer A, Presumey J, Hoffmann M, Koenders MI, Escriou V, Apparailly F, Steiner G. Inhibition of Inflammation and Bone Erosion by RNA Interference–Mediated Silencing of Heterogeneous Nuclear RNP A2/B1 in Two Experimental Models of Rheumatoid Arthritis . Arthritis & Rheumatology . 67 . 9 . 2536–2546 . 2015 . 26017221 . 10.1002/art.39223. free .
• Kentaro I, Shinji K, Shoko U, Akihito M, Nozomi O, Tatsuki S, Senko T, Tomoe K, Yoichi T, Kengo M, Takao Y, Shingo D, Isamu S, Fumio S . Ridaifen G, tamoxifen analog, is a potent anticancer drug working through a combinatorial association with multiple cellular factors . Bioorganic & Medicinal Chemistry . 23 . 18 . 6118–6124 . 2015 . 26314924 . 10.1016/j.bmc.2015.08.001 .
• Geissler R, Simkin A, Floss D, Patel R, Fogarty EA, Scheller J, Grimson A . A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1 . Genes & Development. 30 . 9 . 1070–1085 . 2016 . 27151978 . 10.1101/gad.277392.116 . 4863738.
• QU XH, LIU JL, ZHONG XW, LI X, ZHANG QG . Insights into the roles of hnRNP A2/B1 and AXL in non-small cell lung cancer . Oncology Letters . 10 . 3 . 1677–1685 . 2015 . 26622731 . 10.3892/ol.2015.3457 . 4533760.
• Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF . HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events . Cell . 162. 6 . 1299–1308 . 2015 . 26321680 . 10.1016/j.cell.2015.08.011 . 4673968.

Notes and References

1. Biamonti G, Ruggiu M, Saccone S, Della Valle G, Riva S . Two homologous genes, originated by duplication, encode the human hnRNP proteins A2 and A1 . Nucleic Acids Res. . 22 . 11 . 1996–2002 . Aug 1994 . 8029005 . 308112 . 10.1093/nar/22.11.1996 .
2. Web site: Error 403.
3. Web site: Entrez Gene: HNRPA2B1 heterogeneous nuclear ribonucleoprotein A2/B1.
4. Web site: HNRNPA2B1 heterogeneous nuclear ribonucleoprotein A2/B1 [Homo sapiens (human)] – Gene – NCBI.
5. Web site: Error 403.
6. Munkácsy. Gyöngyi. Sztupinszki. Zsófia. Herman. Péter. Bán. Bence. Pénzváltó. Zsófia. Szarvas. Nóra. Győrffy. Balázs. 2016-01-01. Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments. Molecular Therapy: Nucleic Acids. en. 5. 9. 10.1038/mtna.2016.66. 2162-2531. 5056990. 27673562. e366.
7. Pancetti F, Bosser R, Krehan A, Pyerin W, Itarte E, Bachs O . Heterogeneous nuclear ribonucleoprotein A2 interacts with protein kinase CK2 . Biochem. Biophys. Res. Commun. . 260 . 1 . 17–22 . Jun 1999 . 10381337 . 10.1006/bbrc.1999.0849 .
8. 3756911 . 23455423 . 10.1038/nature11922 . 495 . 7442 . Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS . 2013 . Nature . 467–73 . Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP. 2013Natur.495..467K .
9. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, et al.Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 causemultisystem proteinopathy and ALS. Nature 2013;495:467–73. Available from: https://www.researchgate.net/publication/235770144_Mutations_in_prion-like_domains_in_hnRNPA2B1_and_hnRNPA1_cause_multisystem_proteinopathy_and_ALS [Retrieved 28 Mar 2017].
10. Xuan Yang, Wang Jingshu, Ban Liying, Lu Jian-Jun, Yi Canhui, Li Zhenglin, Yu Wendan, Li Mei, Xu Tingting, Yang Wenjing, Tang Zhipeng, Tang Ranran, Xiao Xiangsheng, Meng Songshu, Chen Yiming, Liu Quentin, Huang Wenlin, Guo Wei, Cui Xiaonan, Deng Wuguo, (2016), hnRNPA2/B1 activates cyclooxygenase-2 and promotes tumor growth in human lung cancers, Molecular Oncology, 10, doi: 10.1016/j.molonc.2015.11.010. Available from: http://onlinelibrary.wiley.com/doi/10.1016/j.molonc.2015.11.010/abstract;jsessionid=F7FAA0EE2ECB0751450320F2792BFD9E.f03t01