2. Academic Validation
  3. HIV protease cleaves the antiviral m6A reader protein YTHDF3 in the viral particle

HIV protease cleaves the antiviral m6A reader protein YTHDF3 in the viral particle

  • PLoS Pathog. 2020 Feb 13;16(2):e1008305. doi: 10.1371/journal.ppat.1008305.
Denise Jurczyszak 1 2,  Wen Zhang 3,  Sandra N Terry 2,  Thomas Kehrer 2,  Maria C Bermúdez González 2,  Emma McGregor 1 2,  Lubbertus C F Mulder 2 4,  Matthew J Eckwahl 5,  Tao Pan 5,  Viviana Simon 2 4 6
Affiliations

Affiliations

  • 1 The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United State of America.
  • 2 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
  • 3 Department of Chemistry, The University of Chicago, Chicago, Illinois, United State of America.
  • 4 Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United State of America.
  • 5 Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois, United State of America.
  • 6 Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United State of America.
PMID: 32053707 DOI: 10.1371/journal.ppat.1008305
Abstract

N6-methyladenosine (m6A) is the most abundant HIV RNA modification but the interplay between the m6A reader protein YTHDF3 and HIV replication is not well understood. We found that knockout of YTHDF3 in human CD4+ T-cells increases Infection supporting the role of YTHDF3 as a restriction factor. Overexpression of the YTHDF3 protein in the producer cells reduces the infectivity of the newly produced viruses. YTHDF3 proteins are incorporated into HIV particles in a nucleocapsid-dependent manner permitting the m6A reader protein to limit Infection in the new target cell at the step of reverse transcription. Importantly, HIV Protease cleaves the virion-incorporated full-length YTHDF3 protein, a process which is blocked by HIV Protease Inhibitors used to treat HIV infected patients. Mass-spectrometry confirmed the proteolytic processing of YTHDF3 in the virion. Thus, HIV Protease cleaves the virion-encapsidated host m6A effector protein in addition to the viral polyproteins to ensure optimal infectivity of the mature virion.

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