Post-translational Modifications of HnRNP A1 Differentially Modulate Retroviral IRES-mediated Translation Initiation

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2020 Sep 22

PMID 32960212

Citations 20

Authors

Aldo Barrera

Hade Ramos

Jorge Vera-Otarola

Leandro Fernandez-Garcia

Jenniffer Angulo

Valeria Olguin

Karla Pino

Andrew J Mouland

Marcelo Lopez-Lastra

Affiliations

Soon will be listed here.

Abstract

The full-length mRNAs of the human immunodeficiency virus type-1 (HIV-1), the human T-cell lymphotropic virus type-1 (HTLV-1), and the mouse mammary tumor virus (MMTV) harbor IRESs. The activity of the retroviral-IRESs requires IRES-transacting factors (ITAFs), being hnRNP A1, a known ITAF for the HIV-1 IRES. In this study, we show that hnRNP A1 is also an ITAF for the HTLV-1 and MMTV IRESs. The MMTV IRES proved to be more responsive to hnRNP A1 than either the HTLV-1 or the HIV-1 IRESs. The impact of post-translational modifications of hnRNP A1 on HIV-1, HTLV-1 and MMTV IRES activity was also assessed. Results show that the HIV-1 and HTLV-1 IRESs were equally responsive to hnRNP A1 and its phosphorylation mutants S4A/S6A, S4D/S6D and S199A/D. However, the S4D/S6D mutant stimulated the activity from the MMTV-IRES to levels significantly higher than the wild type hnRNP A1. PRMT5-induced symmetrical di-methylation of arginine residues of hnRNP A1 enabled the ITAF to stimulate the HIV-1 and HTLV-1 IRESs while reducing the stimulatory ability of the ITAF over the MMTV IRES. We conclude that retroviral IRES activity is not only dependent on the recruited ITAFs but also relies on how these proteins are modified at the post-translational level.

Citing Articles

Enhanced identification of small molecules binding to hnRNPA1 via cryptic pockets mapping coupled with X-Ray fragment screening.

Dunnett L, Das S, Venditti V, Prischi F bioRxiv. 2025; .

PMID: 39763864 PMC: 11702612. DOI: 10.1101/2024.12.17.628909.

The Polypyrimidine Tract-Binding Protein Is a Transacting Factor for the Dengue Virus Internal Ribosome Entry Site.

Fernandez-Garcia L, Angulo J, Lopez-Lastra M Viruses. 2024; 16(11).

PMID: 39599871 PMC: 11599071. DOI: 10.3390/v16111757.

Higher isoform of hnRNPA1 confer Temozolomide resistance in U87MG & LN229 glioma cells.

Bhardwaj S, Sanjay , Yadav A J Neurooncol. 2024; 171(1):47-63.

PMID: 39585598 DOI: 10.1007/s11060-024-04831-y.

Thermodynamic coupling of the tandem RRM domains of hnRNP A1 underlie its pleiotropic RNA binding functions.

Levengood J, Potoyan D, Penumutchu S, Kumar A, Zhou Q, Wang Y Sci Adv. 2024; 10(28):eadk6580.

PMID: 38985864 PMC: 11235170. DOI: 10.1126/sciadv.adk6580.

The Steamer-like Element-1 Retrotransposon Antisense mRNA Harbors an Internal Ribosome Entry Site That Is Modulated by hnRNPK.

Fernandez-Garcia L, Ahumada-Marchant C, Lobos-Avila P, Brauer B, Bustos F, Arriagada G Viruses. 2024; 16(3).

PMID: 38543768 PMC: 10974842. DOI: 10.3390/v16030403.

References

Castello A, Franco D, Moral-Lopez P, Berlanga J, Alvarez E, Wimmer E . HIV- 1 protease inhibits Cap- and poly(A)-dependent translation upon eIF4GI and PABP cleavage. PLoS One. 2009; 4(11):e7997. PMC: 2776998. DOI: 10.1371/journal.pone.0007997. View

Goh W, Rogel M, Kinsey C, Michael S, Fultz P, Nowak M . HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo. Nat Med. 1998; 4(1):65-71. DOI: 10.1038/nm0198-065. View

Lund N, Milev M, Wong R, Sanmuganantham T, Woolaway K, Chabot B . Differential effects of hnRNP D/AUF1 isoforms on HIV-1 gene expression. Nucleic Acids Res. 2011; 40(8):3663-75. PMC: 3333888. DOI: 10.1093/nar/gkr1238. View

Vallejos M, Carvajal F, Pino K, Navarrete C, Ferres M, Huidobro-Toro J . Functional and structural analysis of the internal ribosome entry site present in the mRNA of natural variants of the HIV-1. PLoS One. 2012; 7(4):e35031. PMC: 3319624. DOI: 10.1371/journal.pone.0035031. View

Jablonski J, Caputi M . Role of cellular RNA processing factors in human immunodeficiency virus type 1 mRNA metabolism, replication, and infectivity. J Virol. 2008; 83(2):981-92. PMC: 2612387. DOI: 10.1128/JVI.01801-08. View

Martin J, Masri J, Cloninger C, Holmes B, Artinian N, Funk A . Phosphomimetic substitution of heterogeneous nuclear ribonucleoprotein A1 at serine 199 abolishes AKT-dependent internal ribosome entry site-transacting factor (ITAF) function via effects on strand annealing and results in mammalian target of.... J Biol Chem. 2011; 286(18):16402-13. PMC: 3091246. DOI: 10.1074/jbc.M110.205096. View

Korlimbinis A, Berry Y, Thibault D, Schey K, Truscott R . Protein aging: truncation of aquaporin 0 in human lens regions is a continuous age-dependent process. Exp Eye Res. 2009; 88(5):966-73. PMC: 2713177. DOI: 10.1016/j.exer.2008.12.008. View

Morales Y, Caceres T, May K, Hevel J . Biochemistry and regulation of the protein arginine methyltransferases (PRMTs). Arch Biochem Biophys. 2015; 590:138-152. DOI: 10.1016/j.abb.2015.11.030. View

Lawson J, Salmons B, Glenn W . Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein-Barr Virus (EBV). Front Oncol. 2018; 8:1. PMC: 5786831. DOI: 10.3389/fonc.2018.00001. View

10.

Alvarez E, Castello A, Menendez-Arias L, Carrasco L . HIV protease cleaves poly(A)-binding protein. Biochem J. 2006; 396(2):219-26. PMC: 1462710. DOI: 10.1042/BJ20060108. View

11.

Filbin M, Kieft J . Toward a structural understanding of IRES RNA function. Curr Opin Struct Biol. 2009; 19(3):267-76. PMC: 2757110. DOI: 10.1016/j.sbi.2009.03.005. View

12.

Cinti A, Le Sage V, Milev M, Valiente-Echeverria F, Crossie C, Miron M . HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases. Sci Rep. 2017; 7(1):5515. PMC: 5511174. DOI: 10.1038/s41598-017-05410-0. View

13.

Perales C, Carrasco L, Ventoso I . Cleavage of eIF4G by HIV-1 protease: effects on translation. FEBS Lett. 2002; 533(1-3):89-94. DOI: 10.1016/s0014-5793(02)03764-x. View

14.

Kim H, Lee H, Seo J, Ryu H, Lee K, Kim D . Heterogeneous nuclear ribonucleoprotein A1 regulates rhythmic synthesis of mouse Nfil3 protein via IRES-mediated translation. Sci Rep. 2017; 7:42882. PMC: 5318856. DOI: 10.1038/srep42882. View

15.

Jean-Philippe J, Paz S, Caputi M . hnRNP A1: the Swiss army knife of gene expression. Int J Mol Sci. 2013; 14(9):18999-9024. PMC: 3794818. DOI: 10.3390/ijms140918999. View

16.

Lewis S, Holcik M . For IRES trans-acting factors, it is all about location. Oncogene. 2007; 27(8):1033-5. DOI: 10.1038/sj.onc.1210777. View

17.

Bell N, Lever A . HIV Gag polyprotein: processing and early viral particle assembly. Trends Microbiol. 2012; 21(3):136-44. DOI: 10.1016/j.tim.2012.11.006. View

18.

Valiente-Echeverria F, Vallejos M, Monette A, Pino K, Letelier A, Huidobro-Toro J . A cis-acting element present within the Gag open reading frame negatively impacts on the activity of the HIV-1 IRES. PLoS One. 2013; 8(2):e56962. PMC: 3581557. DOI: 10.1371/journal.pone.0056962. View

19.

Caceres C, Contreras N, Angulo J, Vera-Otarola J, Pino-Ajenjo C, Llorian M . Polypyrimidine tract-binding protein binds to the 5' untranslated region of the mouse mammary tumor virus mRNA and stimulates cap-independent translation initiation. FEBS J. 2016; 283(10):1880-901. DOI: 10.1111/febs.13708. View

20.

Vallejos M, Ramdohr P, Valiente-Echeverria F, Tapia K, Rodriguez F, Lowy F . The 5'-untranslated region of the mouse mammary tumor virus mRNA exhibits cap-independent translation initiation. Nucleic Acids Res. 2009; 38(2):618-32. PMC: 2811009. DOI: 10.1093/nar/gkp890. View