Methylation of Tat by PRMT6 Regulates Human Immunodeficiency Virus Type 1 Gene Expression

Author:

Boulanger Marie-Chloé12,Liang Chen3,Russell Rodney S.34,Lin Rongtuan15,Bedford Mark T.6,Wainberg Mark A.34,Richard Stéphane1257

Affiliation:

1. Terry Fox Molecular Oncology Group

2. Bloomfield Center for Research on Aging

3. McGill University AIDS Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital

4. Departments of Microbiology

5. Medicine

6. M.D. Anderson Cancer Center, Department of Carcinogenesis, University of Texas, Smithville, Texas

7. Oncology, McGill University, Montréal, Québec, Canada

Abstract

ABSTRACT The human immunodeficiency virus (HIV) transactivator protein, Tat, stimulates transcription from the viral long terminal repeats via an arginine-rich transactivating domain. Since arginines are often known to be methylated, we investigated whether HIV type 1 (HIV-1) Tat was a substrate for known protein arginine methyltransferases (PRMTs). Here we identify Tat as a substrate for the arginine methyltransferase, PRMT6. Tat is specifically associated with and methylated by PRMT6 within cells. Overexpression of wild-type PRMT6, but not a methylase-inactive PRMT6 mutant, decreased Tat transactivation of an HIV-1 long terminal repeat luciferase reporter plasmid in a dose-dependent manner. Knocking down PRMT6 consistently increased HIV-1 production in HEK293T cells and also led to increased viral infectiousness as shown in multinuclear activation of a galactosidase indicator assays. Our study demonstrates that arginine methylation of Tat negatively regulates its transactivation activity and that PRMT6 acts as a restriction factor for HIV replication.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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