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

Qiong Zhang, Yuqi Kang, Shaobo Wang, Gwendolyn Michelle Gonzalez, Wanyu Li, Hui Hui, Yinsheng Wang and Tariq M. Rana ()
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Qiong Zhang: University of California San Diego School of Medicine
Yuqi Kang: University of California San Diego School of Medicine
Shaobo Wang: University of California San Diego School of Medicine
Gwendolyn Michelle Gonzalez: University of California
Wanyu Li: University of California San Diego School of Medicine
Hui Hui: University of California San Diego School of Medicine
Yinsheng Wang: University of California
Tariq M. Rana: University of California San Diego School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract N6,2′-O-dimethyladenosine (m6Am) is an abundant RNA modification located adjacent to the 5′-end of the mRNA 7-methylguanosine (m7G) cap structure. m6A 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 m6Am and the function of PCIF1 in regulating host–pathogens interactions are unknown. Here, we investigate the dynamics and reprogramming of the host m6Am RNA methylome during HIV infection. We show that HIV infection induces a dramatic decrease in m6Am of cellular mRNAs. By using PCIF1 depleted T cells, we identify 2237 m6Am 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 m6Am 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 m6Am modified genes in T cells which are affected by viral infection, and reveals how HIV regulates host RNA epitranscriptomics through PCIF1 degradation.

Date: 2021
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DOI: 10.1038/s41467-021-25683-4

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