HIV-1 hypermethylated guanosine cap licenses specialized translation unaffected by mTOR

Gatikrushna Singh, Bradley Seufzer, Zhenwei Song, Dora Zucko, Xiao Heng, Kathleen Boris-Lawrie

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Appended to the 5' end of nascent RNA polymerase II transcripts is 7-methyl guanosine (m 7G-cap) that engages nuclear cap-binding complex (CBC) to facilitate messenger RNA (mRNA) maturation. Mature mRNAs exchange CBC for eIF4E, the rate-limiting translation factor that is controlled through mTOR. Experiments in immune cells have now documented HIV-1 incompletely processed transcripts exhibited hypermethylated m 7G-cap and that the down-regulation of the trimethylguanosine synthetase-1-reduced HIV-1 infectivity and virion protein synthesis by several orders of magnitude. HIV-1 cap hypermethylation required nuclear RNA helicase A (RHA)/DHX9 interaction with the shape of the 5' untranslated region (UTR) primer binding site (PBS) segment. Down-regulation of RHA or the anomalous shape of the PBS segment abrogated hypermethylated caps and derepressed eIF4E binding for virion protein translation during global down-regulation of host translation. mTOR inhibition was detrimental to HIV-1 proliferation and attenuated Tat, Rev, and Nef synthesis. This study identified mutually exclusive translation pathways and the calibration of virion structural/accessory protein synthesis with de novo synthesis of the viral regulatory proteins. The hypermethylation of select, viral mRNA resulted in CBC exchange to heterodimeric CBP80/NCBP3 that expanded the functional capacity of HIV-1 in immune cells.

Original languageEnglish (US)
Article numbere2105153118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number1
DOIs
StatePublished - Jan 4 2022

Bibliographical note

Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.

Keywords

  • EIF4E inactivation
  • M7G-cap methylation
  • Nuclear RNA helicase
  • RNA fate
  • Virus–host interaction

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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