Journal article
HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication
Journal of virology, Vol.91(21), e01240-17
11/01/2017
DOI: 10.1128/JVI.01240-17
PMCID: PMC5640844
PMID: 28814526
Abstract
A hallmark of retroviruses such as human immunodeficiency virus type 1 (HIV-1) is reverse transcription of genomic RNA to DNA, a process that is primed by cellular tRNAs. HIV-1 recruits human tRNA
to serve as the reverse transcription primer via an interaction between lysyl-tRNA synthetase (LysRS) and the HIV-1 Gag polyprotein. LysRS is normally sequestered in a multi-aminoacyl-tRNA synthetase complex (MSC). Previous studies demonstrated that components of the MSC can be mobilized in response to certain cellular stimuli, but how LysRS is redirected from the MSC to viral particles for packaging is unknown. Here, we show that upon HIV-1 infection, a free pool of non-MSC-associated LysRS is observed and partially relocalized to the nucleus. Heat inactivation of HIV-1 blocks nuclear localization of LysRS, but treatment with a reverse transcriptase inhibitor does not, suggesting that the trigger for relocalization occurs prior to reverse transcription. A reduction in HIV-1 infection is observed upon treatment with an inhibitor to mitogen-activated protein kinase that prevents phosphorylation of LysRS on Ser207, release of LysRS from the MSC, and nuclear localization. A phosphomimetic mutant of LysRS (S207D) that lacked the capability to aminoacylate tRNA
localized to the nucleus, rescued HIV-1 infectivity, and was packaged into virions. In contrast, a phosphoablative mutant (S207A) remained cytosolic and maintained full aminoacylation activity but failed to rescue infectivity and was not packaged. These findings suggest that HIV-1 takes advantage of the dynamic nature of the MSC to redirect and coopt cellular translation factors to enhance viral replication.
Human tRNA
, the primer for reverse transcription, and LysRS are essential host factors packaged into HIV-1 virions. Previous studies found that tRNA
packaging depends on interactions between LysRS and HIV-1 Gag; however, many details regarding the mechanism of tRNA
and LysRS packaging remain unknown. LysRS is normally sequestered in a high-molecular-weight multi-aminoacyl-tRNA synthetase complex (MSC), restricting the pool of free LysRS-tRNA
Mounting evidence suggests that LysRS is released under a variety of stimuli to perform alternative functions within the cell. Here, we show that HIV-1 infection results in a free pool of LysRS that is relocalized to the nucleus of target cells. Blocking this pathway in HIV-1-producing cells resulted in less infectious progeny virions. Understanding the mechanism by which LysRS is recruited into the viral assembly pathway can be exploited for the development of specific and effective therapeutics targeting this nontranslational function.
Details
- Title: Subtitle
- HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication
- Creators
- Alice A Duchon - Center for RNA Biology, Ohio State University, Columbus, Ohio, USACorine St Gelais - Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio, USANathan Titkemeier - Center for RNA Biology, Ohio State University, Columbus, Ohio, USAJoshua Hatterschide - Center for RNA Biology, Ohio State University, Columbus, Ohio, USALi Wu - Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio, USAKarin Musier-Forsyth - Center for RNA Biology, Ohio State University, Columbus, Ohio, USA
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.91(21), e01240-17
- Publisher
- United States
- DOI
- 10.1128/JVI.01240-17
- PMID
- 28814526
- PMCID
- PMC5640844
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Grant note
- R01 AI104483 / NIAID NIH HHS R01 GM113887 / NIGMS NIH HHS F31 GM119178 / NIGMS NIH HHS
- Language
- English
- Date published
- 11/01/2017
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984001161102771
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