HIV reprograms host m(6)Am RNA methylome by viral Vpr protein-mediated degradation of PCIF1

Zhang, Qiong; Kang, Yuqi; Wang, Shaobo; Gonzalez, Gwendolyn Michelle; Li, Wanyu; Hui, Hui; Wang, Yinsheng; Rana, Tariq M.

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.