Journal article
N 6 -Methyladenosine-binding proteins suppress HIV-1 infectivity and viral production
The Journal of biological chemistry, Vol.293(34), pp.12992-13005
08/24/2018
DOI: 10.1074/jbc.RA118.004215
PMCID: PMC6109920
PMID: 29976753
Abstract
The internal
-methyladenosine (m
A) modification of cellular mRNA regulates post-transcriptional gene expression. The YTH domain family proteins (YTHDF1-3 or Y1-3) bind to m
A-modified cellular mRNAs and modulate their metabolism and processing, thereby affecting cellular protein translation. We previously reported that HIV-1 RNA contains the m
A modification and that Y1-3 proteins inhibit HIV-1 infection by decreasing HIV-1 reverse transcription activity. Here, we investigated the mechanisms of Y1-3-mediated inhibition of HIV-1 infection in target cells and the effect of Y1-3 on viral production levels in virus-producing cells. We found that Y1-3 protein overexpression in HIV-1 target cells decreases viral genomic RNA (gRNA) levels and inhibits both early and late reverse transcription. Purified recombinant Y1-3 proteins preferentially bound to the m
A-modified 5' leader sequence of gRNA compared with its unmodified RNA counterpart, consistent with the strong binding of Y1-3 proteins to HIV-1 gRNA in infected cells. HIV-1 mutants with two altered m
A modification sites in the 5' leader sequence of gRNA exhibited significantly lower infectivity than WT, replication-competent HIV-1, confirming that these sites alter viral infection. HIV-1 produced from cells in which endogenous Y1, Y3, or Y1-3 proteins were knocked down singly or together had increased viral infectivity compared with HIV-1 produced in control cells. Interestingly, we found that Y1-3 proteins and HIV-1 Gag protein formed a complex with RNA in HIV-1-producing cells. Overall, these results indicate that Y1-3 proteins inhibit HIV-1 infection and provide new insights into the mechanisms by which the m
A modification of HIV-1 RNA affects viral replication.
Details
- Title: Subtitle
- N 6 -Methyladenosine-binding proteins suppress HIV-1 infectivity and viral production
- Creators
- Wuxun Lu - From the Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43210Nagaraja Tirumuru - From the Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43210Corine St Gelais - From the Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43210Pratibha C Koneru - the Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado 80045, andChang Liu - Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637Mamuka Kvaratskhelia - the Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado 80045, andChuan He - Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637Li Wu - From the Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43210, wu.840@osu.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(34), pp.12992-13005
- DOI
- 10.1074/jbc.RA118.004215
- PMID
- 29976753
- PMCID
- PMC6109920
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- United States
- Grant note
- R01 AI062520 / NIAID NIH HHS R01 GM128212 / NIGMS NIH HHS
- Language
- English
- Date published
- 08/24/2018
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984001222602771
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