Regulation of HIV-1 Gag-Pol Expression by Shiftless, an Inhibitor of Programmed -1 Ribosomal Frameshifting

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Jan 26

PMID 30682371

Citations 71

Authors

Xinlu Wang

Yifang Xuan

Yuling Han

Xiang Ding

Kai Ye

Fuquan Yang

Pu Gao

Stephen P Goff

Guangxia Gao

Affiliations

Soon will be listed here.

Abstract

Programmed -1 ribosomal frameshifting (-1PRF) is a widely used translation recoding mechanism. HIV-1 expresses Gag-Pol protein from the Gag-coding mRNA through -1PRF, and the ratio of Gag to Gag-Pol is strictly maintained for efficient viral replication. Here, we report that the interferon-stimulated gene product C19orf66 (herein named Shiftless) is a host factor that inhibits the -1PRF of HIV-1. Shiftless (SFL) also inhibited the -1PRF of a variety of mRNAs from both viruses and cellular genes. SFL interacted with the -1PRF signal of target mRNA and translating ribosomes and caused premature translation termination at the frameshifting site. Downregulation of translation release factor eRF3 or eRF1 reduced SFL-mediated premature translation termination. We propose that SFL binding to target mRNA and the translating ribosome interferes with the frameshifting process. These findings identify SFL as a broad-spectrum inhibitor of -1PRF and help to further elucidate the mechanisms of -1PRF.

Citing Articles

Regulation of viral replication by host restriction factors.

Lin Y, Zhu Y, Jing L, Lei X, Xie Z Front Immunol. 2025; 16:1484119.

PMID: 39917304 PMC: 11798991. DOI: 10.3389/fimmu.2025.1484119.

Host RNA-Binding Proteins as Regulators of HIV-1 Replication.

Giraldo-Ocampo S, Valiente-Echeverria F, Soto-Rifo R Viruses. 2025; 17(1).

PMID: 39861832 PMC: 11768693. DOI: 10.3390/v17010043.

Viral RNA Interactome: The Ultimate Researcher's Guide to RNA-Protein Interactions.

Hanson W, Romero Agosto G, Rouskin S Viruses. 2024; 16(11).

PMID: 39599817 PMC: 11599142. DOI: 10.3390/v16111702.

Imaging and Quantifying Ribosomal Frameshifting Dynamics with Single-RNA Precision in Live Cells.

Lyon K, Morisaki T, Stasevich T Methods Mol Biol. 2024; 2875:99-110.

PMID: 39535643 PMC: 11633442. DOI: 10.1007/978-1-0716-4248-1_9.

Help or Hinder: Protein Host Factors That Impact HIV-1 Replication.

Moezpoor M, Stevenson M Viruses. 2024; 16(8).

PMID: 39205255 PMC: 11360189. DOI: 10.3390/v16081281.

References

Kim Y, Maas S, Rich A . Comparative mutational analysis of cis-acting RNA signals for translational frameshifting in HIV-1 and HTLV-2. Nucleic Acids Res. 2001; 29(5):1125-31. PMC: 29715. DOI: 10.1093/nar/29.5.1125. View

Ramsey J, Mukhopadhyay S . Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins. Viruses. 2017; 9(8). PMC: 5580485. DOI: 10.3390/v9080228. View

Yoshinaka Y, Katoh I, Copeland T, Oroszlan S . Murine leukemia virus protease is encoded by the gag-pol gene and is synthesized through suppression of an amber termination codon. Proc Natl Acad Sci U S A. 1985; 82(6):1618-22. PMC: 397323. DOI: 10.1073/pnas.82.6.1618. View

Xuan Y, Gong D, Qi J, Han C, Deng H, Gao G . ZAP inhibits murine gammaherpesvirus 68 ORF64 expression and is antagonized by RTA. J Virol. 2012; 87(5):2735-43. PMC: 3571413. DOI: 10.1128/JVI.03015-12. View

Marcheschi R, Staple D, Butcher S . Programmed ribosomal frameshifting in SIV is induced by a highly structured RNA stem-loop. J Mol Biol. 2007; 373(3):652-63. PMC: 2080864. DOI: 10.1016/j.jmb.2007.08.033. View

Chamorro M, Parkin N, Varmus H . An RNA pseudoknot and an optimal heptameric shift site are required for highly efficient ribosomal frameshifting on a retroviral messenger RNA. Proc Natl Acad Sci U S A. 1992; 89(2):713-7. PMC: 48309. DOI: 10.1073/pnas.89.2.713. View

Snyder J, Kulcsar K, Schultz K, Riley C, Neary J, Marr S . Functional characterization of the alphavirus TF protein. J Virol. 2013; 87(15):8511-23. PMC: 3719798. DOI: 10.1128/JVI.00449-13. View

Hung M, Patel P, Davis S, Green S . Importance of ribosomal frameshifting for human immunodeficiency virus type 1 particle assembly and replication. J Virol. 1998; 72(6):4819-24. PMC: 110024. DOI: 10.1128/JVI.72.6.4819-4824.1998. View

Goujon C, Moncorge O, Bauby H, Doyle T, Ward C, Schaller T . Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature. 2013; 502(7472):559-62. PMC: 3808269. DOI: 10.1038/nature12542. View

10.

Wang X, Li M, Zhao J, Li S, MacDonald M, Rice C . Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance. J Virol. 2016; 90(22):10247-10258. PMC: 5105660. DOI: 10.1128/JVI.01487-16. View

11.

Chen J, Petrov A, Johansson M, Tsai A, OLeary S, Puglisi J . Dynamic pathways of -1 translational frameshifting. Nature. 2014; 512(7514):328-32. PMC: 4472451. DOI: 10.1038/nature13428. View

12.

Wills N, Moore B, Hammer A, Gesteland R, Atkins J . A functional -1 ribosomal frameshift signal in the human paraneoplastic Ma3 gene. J Biol Chem. 2006; 281(11):7082-8. DOI: 10.1074/jbc.M511629200. View

13.

Kim H, Liu F, Fei J, Bustamante C, Gonzalez Jr R, Tinoco Jr I . A frameshifting stimulatory stem loop destabilizes the hybrid state and impedes ribosomal translocation. Proc Natl Acad Sci U S A. 2014; 111(15):5538-43. PMC: 3992627. DOI: 10.1073/pnas.1403457111. View

14.

Choi J, Xu Z, Ou J . Triple decoding of hepatitis C virus RNA by programmed translational frameshifting. Mol Cell Biol. 2003; 23(5):1489-97. PMC: 151691. DOI: 10.1128/MCB.23.5.1489-1497.2003. View

15.

Plant E, Wang P, Jacobs J, Dinman J . A programmed -1 ribosomal frameshift signal can function as a cis-acting mRNA destabilizing element. Nucleic Acids Res. 2004; 32(2):784-90. PMC: 373365. DOI: 10.1093/nar/gkh256. View

16.

Dulude D, Berchiche Y, Gendron K, Brakier-Gingras L, Heveker N . Decreasing the frameshift efficiency translates into an equivalent reduction of the replication of the human immunodeficiency virus type 1. Virology. 2005; 345(1):127-36. DOI: 10.1016/j.virol.2005.08.048. View

17.

Atkins J, Loughran G, Bhatt P, Firth A, Baranov P . Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use. Nucleic Acids Res. 2016; 44(15):7007-78. PMC: 5009743. DOI: 10.1093/nar/gkw530. View

18.

Belew A, Dinman J . Cell cycle control (and more) by programmed -1 ribosomal frameshifting: implications for disease and therapeutics. Cell Cycle. 2015; 14(2):172-8. PMC: 4615106. DOI: 10.4161/15384101.2014.989123. View

19.

Napthine S, Ling R, Finch L, Jones J, Bell S, Brierley I . Protein-directed ribosomal frameshifting temporally regulates gene expression. Nat Commun. 2017; 8:15582. PMC: 5472766. DOI: 10.1038/ncomms15582. View

20.

Yan S, Wen J, Bustamante C, Tinoco Jr I . Ribosome excursions during mRNA translocation mediate broad branching of frameshift pathways. Cell. 2015; 160(5):870-881. PMC: 4344849. DOI: 10.1016/j.cell.2015.02.003. View