Acetylation of Cytidine Residues Boosts HIV-1 Gene Expression by Increasing Viral RNA Stability

University of North Carolina (UNC) at Chapel Hill - Lineberger Comprehensive Cancer Center; University of North Carolina (UNC) at Chapel Hill - Department of Biochemistry and Biophysics

Bryan R. Cullen

Duke University - Department of Molecular Genetics & Microbiology

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Abstract

Epitranscriptomic RNA modifications, including methylation of A and C residues, are now recognized as key regulators of both cellular and viral mRNA function. Moreover, acetylation of the N⁴ position of cytidine (ac4C) was recently reported to increase the translation and stability of cellular mRNAs. Here, we show that ac4C and N-acetyltransferase 10 (NAT10), the enzyme that adds ac4C to RNAs, have been subverted by human immunodeficiency virus 1 (HIV-1) to increase viral gene expression. HIV-1 transcripts are modified with ac4C at multiple discreet sites, and silent mutagenesis of these ac4C sites led to decreased HIV-1 gene expression. Similarly, loss of ac4C from viral transcripts due to depletion of NAT10 inhibited HIV-1 replication by reducing viral RNA stability. Interestingly, the NAT10 inhibitor Remodelin could inhibit HIV-1 replication at levels that have no effect on cell viability, thus identifying ac4C addition as a potential novel target for antiviral drug development.

Keywords: HIV-1, Human immunodeficiency virus 1, retrovirus, virus, gene regulation, epitranscriptomic, RNA modification, ac4C, N4-acetylcytidine, NAT10, N-acetyltransferase 10

Suggested Citation: Suggested Citation

Tsai, Kevin and Vasudevan, Ananda Ayyappan Jaguva and Campos, Cecilia Martinez and Emery, Ann and Swanstrom, Ronald and Cullen, Bryan R., Acetylation of Cytidine Residues Boosts HIV-1 Gene Expression by Increasing Viral RNA Stability. Available at SSRN: https://ssrn.com/abstract=3565021 or http://dx.doi.org/10.2139/ssrn.3565021

This version of the paper has not been formally peer reviewed.