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Journal of Virology, November 2009, p. 11694-11703, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.00499-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Arginine Methylation Increases the Stability of Human Immunodeficiency Virus Type 1 Tat{triangledown}

Haran Sivakumaran,1,3 Armando van der Horst,2 Alex J. Fulcher,4 Ann Apolloni,1 Min-Hsuan Lin,1 David A. Jans,4 and David Harrich1,5*

Division of Infectious Diseases,1 Division of Cancer and Cell Biology, Queensland Institute of Medical Research, Herston, Queensland 4006, Australia,2 The University of Queensland, School of Population Health, Herston, Queensland 4072, Australia,3 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia,4 Griffith Medical Research College, a Joint Program of Griffith University and the Queensland Institute of Medical Research, Queensland, Australia5

Received 11 March 2009/ Accepted 25 August 2009

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 REG{gamma}-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.

* Corresponding author. Mailing address: Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia. Phone: 61 7 3845 3679. Fax: 61 7 3362 0107. E-mail: david.harrich{at}qimr.edu.au

{triangledown} Published ahead of print on 2 September 2009.

Journal of Virology, November 2009, p. 11694-11703, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.00499-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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