Methylation of Tat by PRMT6 regulates human immunodeficiency virus type 1 gene expression.
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.
Boulanger
Marie-Chloé
MC
Terry Fox Molecular Oncology Group, Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Canada.
Liang
Chen
C
Russell
Rodney S
RS
Lin
Rongtuan
R
Bedford
Mark T
MT
Wainberg
Mark A
MA
Richard
Stéphane
S
D000595:Amino Acid Sequence; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016655:HIV Core Protein p24 / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016655:HIV Core Protein p24; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D054322:tat Gene Products, Human Immunodeficiency Virus; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases