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Journal of Virology, October 2008, p. 9937-9950, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.00819-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Kinesin KIF4 Regulates Intracellular Trafficking and Stability of the Human Immunodeficiency Virus Type 1 Gag Polyprotein{triangledown} ,{dagger}

Nathaniel W. Martinez,1 Xiaoxiao Xue,2 Reem G. Berro,3 Geri Kreitzer,2 and Marilyn D. Resh1*

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065,1 Department of Cell and Developmental Biology,2 Department of Microbiology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 100653

Received 16 April 2008/ Accepted 26 July 2008

Retroviral Gag proteins are synthesized as soluble, myristoylated precursors that traffic to the plasma membrane and promote viral particle production. The intracellular transport of human immunodeficiency virus type 1 (HIV-1) Gag to the plasma membrane remains poorly understood, and cellular motor proteins responsible for Gag movement are not known. Here we show that disrupting the function of KIF4, a kinesin family member, slowed temporal progression of Gag through its trafficking intermediates and inhibited virus-like particle production. Knockdown of KIF4 also led to increased Gag degradation, resulting in reduced intracellular Gag protein levels; this phenotype was rescued by reintroduction of KIF4. When KIF4 function was blocked, Gag transiently accumulated in discrete, perinuclear, nonendocytic clusters that colocalized with endogenous KIF4, with Ubc9, an E2 SUMO-1 conjugating enzyme, and with SUMO. These studies identify a novel transit station through which Gag traffics en route to particle assembly and highlight the importance of KIF4 in regulating HIV-1 Gag trafficking and stability.

* Corresponding author. Mailing address: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 143, New York, NY 10065. Phone: (212) 639-2514. Fax: (212) 717-3317. E-mail: m-resh{at}ski.mskcc.org

{triangledown} Published ahead of print on 6 August 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, October 2008, p. 9937-9950, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.00819-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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