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

• Published in: Cell host & microbe 2020-08, Vol.28 (2), p.306-312.e6
• Main Authors: Tsai, Kevin, Jaguva Vasudevan, Ananda Ayyappan, Martinez Campos, Cecilia, Emery, Ann, Swanstrom, Ronald, Cullen, Bryan R.
• Format: Article
• Language: English
• Subjects: ac4C; Acetylation - drug effects; Cell Line; Cytidine - metabolism; epitranscriptomic; Female; Gene Expression - drug effects; Gene Expression Regulation, Viral - drug effects; Gene Expression Regulation, Viral - genetics; gene regulation; HEK293 Cells; HIV-1; HIV-1 - genetics; HIV-1 - growth & development; human immunodeficiency virus 1; Humans; Hydrazones - pharmacology; Male; N-acetyltransferase 10; N-Terminal Acetyltransferases - metabolism; N4-acetylcytidine; NAT10; retrovirus; RNA modification; RNA Stability - drug effects; RNA Stability - genetics; RNA, Viral - genetics; Thiazoles - pharmacology; virus; Virus Replication - physiology
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2020.05.011

Epitranscriptomic RNA modifications, including methylation of adenine and cytidine 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 discrete 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 concentrations that have no effect on cell viability, thus identifying ac4C addition as a potential target for antiviral drug development. [Display omitted] •Cytidines on HIV-1 RNAs are acetylated to ac4C by NAT10•Deposition of ac4C residues enhances viral RNA stability•Silent mutagenesis of ac4C sites causes a NAT10-dependent drop in HIV-1 replication•Remodelin, a small molecule NAT10 inhibitor, can inhibit HIV-1 gene expression Tsai et al. report that multiple cytidines on HIV-1 RNAs are acetylated to ac4C by cellular NAT10. Depletion of ac4C by mutagenesis or drug treatment reduces the stability of HIV-1 transcripts, causing reduced viral replication. Thus, HIV-1 has evolved to highjack a host epitranscriptomic modification enzyme to enhance viral replication.