N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression

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Abstract

The internal N⁶-methyladenosine (m⁶A) methylation of eukaryotic nuclear RNA controls post-transcriptional gene expression, which is regulated by methyltransferases (writers), demethylases (erasers), and m⁶A-binding proteins (readers) in cells. The YTH domain family proteins (YTHDF1-3) bind to m⁶A-modified cellular RNAs and affect RNA metabolism and processing. Here we show that YTHDF1-3 proteins recognize m⁶A-modified HIV-1 RNA and inhibit HIV-1 infection in cell lines and primary CD4⁺ T-cells. We further mapped the YTHDF1-3 binding sites in HIV-1 RNA from infected cells. We found that overexpression of YTHDF proteins in cells inhibited HIV-1 infection mainly by decreasing HIV-1 reverse transcription, while knockdown of YTHDF1-3 in cells had the opposite effects. Moreover, silencing the m⁶A writers decreased HIV-1 Gag protein expression in virus-producer cells, while silencing the m⁶A erasers increased Gag expression. Our findings suggest an important role of m⁶A modification of HIV-1 RNA in viral infection and HIV-1 protein synthesis.

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Nagaraja Tirumuru

Center for Retrovirus Research, The Ohio State University, Columbus, United States

Competing interests
The authors declare that no competing interests exist.
Boxuan Simen Zhao

Department of Chemistry, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Wuxun Lu

Center for Retrovirus Research, The Ohio State University, Columbus, United States

Competing interests
The authors declare that no competing interests exist.
Zhike Lu

Department of Chemistry, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Chuan He

Department of Chemistry, The University of Chicago, Chicago, United States

For correspondence
chuanhe@uchicago.edu

Competing interests
The authors declare that no competing interests exist.
Li Wu

Center for Retrovirus Research, The Ohio State University, Columbus, United States

For correspondence
wu.840@osu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5468-2487

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