HIV reprograms host m6Am RNA methylome by viral Vpr protein-mediated degradation of PCIF1

• Published in: Nature communications 2021-09, Vol.12 (1), p.5543-5543, Article 5543
• Main Authors: Zhang, Qiong, Kang, Yuqi, Wang, Shaobo, Gonzalez, Gwendolyn Michelle, Li, Wanyu, Hui, Hui, Wang, Yinsheng, Rana, Tariq M.
• Format: Article
• Language: English
• Subjects: 38; 45; 45/29; 45/70; 45/71; 45/90; 45/91; 631/250/255/1901; 631/337/1645; Degradation; ETS protein; Ets-1 protein; Gene regulation; Genes; HIV; Human immunodeficiency virus; Humanities and Social Sciences; Infections; Lymphocytes; Lymphocytes T; Methyltransferase; multidisciplinary; N6-methyladenosine; Proteins; Replication; Ribonucleic acid; RNA; RNA modification; Science; Science (multidisciplinary); Transcription factors; Ubiquitination; Viral infections; Vpr protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25683-4

N 6 ,2′- O -dimethyladenosine (m 6 Am) is an abundant RNA modification located adjacent to the 5′-end of the mRNA 7-methylguanosine (m 7 G) cap structure. m 6 A methylation on 2′- O -methylated A at the 5′-ends of mRNAs is catalyzed by the methyltransferase Phosphorylated CTD Interacting Factor 1 (PCIF1). The role of m 6 Am and the function of PCIF1 in regulating host–pathogens interactions are unknown. Here, we investigate the dynamics and reprogramming of the host m 6 Am RNA methylome during HIV infection. We show that HIV infection induces a dramatic decrease in m 6 Am of cellular mRNAs. By using PCIF1 depleted T cells, we identify 2237 m 6 Am genes and 854 are affected by HIV infection. Strikingly, we find that PCIF1 methyltransferase function restricts HIV replication. Further mechanism studies show that HIV viral protein R (Vpr) interacts with PCIF1 and induces PCIF1 ubiquitination and degradation. Among the m 6 Am genes, we find that PCIF1 inhibits HIV infection by enhancing a transcription factor ETS1 (ETS Proto-Oncogene 1, transcription factor) stability that binds HIV promoter to regulate viral transcription. Altogether, our study discovers the role of PCIF1 in HIV–host interactions, identifies m 6 Am modified genes in T cells which are affected by viral infection, and reveals how HIV regulates host RNA epitranscriptomics through PCIF1 degradation. m6Am is a modification of the 5′ end of mRNAs catalyzed by PCIF1. Here, Zhang et al. show that HIV infection induces a decrease in m6Am of cellular mRNAs through Vpr-mediated PCIF1 ubiquitination and degradation, resulting in increased HIV replication through regulation of host transcription factors.