Arginine methylation increases the stability of human immunodeficiency virus type 1 Tat.
Arginine methylation of human immunodeficiency virus type 1 (HIV-1) Tat protein downregulates its key function in viral-gene transactivation. The fate of methylated Tat is unknown, so it is unclear whether methylated Tat is degraded or persists in the cell for additional functions. Here we show that the arginine methyltransferase PRMT6 increases Tat protein half-life by 4.7-fold. Tat stabilization depends on the catalytic activity of PRMT6 and requires arginine methylation within the Tat basic domain. In contrast, HIV-1 Rev, which is also methylated by PRMT6, is completely refractory to the stabilizing effect. Proteasome inhibition and silencing experiments demonstrated that Tat can be degraded by a REGgamma-independent proteasome, against which PRMT6 appears to act to increase Tat half-life. Our data reveal a proteasome-dependent Tat degradation pathway that is inhibited by arginine methylation. The stabilizing action of PRMT6 could allow Tat to persist within the cell and the extracellular environment and thereby enable functions implicated in AIDS-related cancer, neurodegeneration, and T-cell death.
Sivakumaran
Haran
H
Division of Infectious Diseases, Queensland Institute of Medical Research, Herston, Queensland 4006, Australia.
van der Horst
Armando
A
Fulcher
Alex J
AJ
Apolloni
Ann
A
Lin
Min-Hsuan
MH
Jans
David A
DA
Harrich
David
D
D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D009687:Nuclear Proteins / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
D009687:Nuclear Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D001120:Arginine; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases