3 years ago

HIV-1 envelope proteins up-regulate N6-methyladenosine levels of cellular RNA independently of viral replication.

Nagaraja Tirumuru, Li Wu
N6-methyladenosine (m6A) modification of HIV-1 RNA regulates viral replication and protein expression. The m6A modification is regulated by two groups of cellular proteins, named writers and erasers that add or remove m6A, respectively. HIV-1 infection of CD4+ T-cells increases m6A levels of cellular mRNA, but the underlying mechanism is unknown.Here, we show that HIV-1 infection of CD4+ primary T-cells or Jurkat cells significantly increases m6A levels of cellular RNA independently of viral replication. Compared with HIV-1-infected CD4+ T cells, similar m6A up-regulation was detected in total RNA from HIV-1-infected cells treated with a reverse transcriptase inhibitor or with heat-inactivated HIV-1. Compared with mock controls, significantly increased m6A levels were detected in total RNA from Jurkat cells infected by single-cycle HIV-1 pseudotyped with an HIV-1 envelope glycoprotein (Env), but not with vesicular stomatitis virus glycoprotein G (VSV-G). Over-expression of HIV-1 Env in HEK293T cells did not affect m6A levels of cellular RNA, suggesting that de novosynthesis of Env is not required for m6A up-regulation. Interestingly, treatment of Jurkat cells with recombinant gp120 of HIV-1 Env significantly increased m6A levels of cellular RNA, which was reduced by a gp120-neutralizing antibody. Pre-incubation of Jurkat cells with a CD4 receptor-neutralizing antibody blocked HIV-1-induced up-regulation of m6A levels in cellular RNA. Moreover, HIV-1 infection or gp120 treatment did not alter the protein expression of m6A writers and erasers in cells. Our findings suggest that HIV-1 gp120 binding to the CD4 receptor is required for m6A up-regulation in cells.

Publisher URL: http://doi.org/10.1074/jbc.RA118.005608

DOI: 10.1074/jbc.RA118.005608

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