Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 1, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2105153118
Keywords
RNA fate; virus-host interaction; m7G-cap methylation; eIF4E inactivation; nuclear RNA
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Funding
- NIH [R01AI150460]
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This study reveals the relationship between incomplete processing and hypermethylation of HIV-1 transcripts, as well as the role of trimethylguanosine synthetase-1 in HIV-1 infectivity and protein synthesis. The study also uncovers the interaction between nuclear RNA helicase A and the shape of the 5' untranslated region primer binding site, and the relationship between HIV-1 virion protein synthesis and host translation.
Appended to the 5' end of nascent RNA polymerase II transcripts is 7-methyl guanosine (m7G-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(7)G-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.
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