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Published 4 August 2003. doi:10.1083/jcb.200302138
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© The Rockefeller University Press, 0021-9525/2003/8/425 $5.00
The Journal of Cell Biology, Volume 162, Number 3, 425-434

Article

 HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein

Owen Pornillos1, Daniel S. Higginson1, Kirsten M. Stray1, Robert D. Fisher1, Jennifer E. Garrus1, Marielle Payne1, Gong-Ping He2, Hubert E. Wang2, Scott G. Morham2 and Wesley I. Sundquist1

1 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84132
2 Myriad Genetics, Salt Lake City, UT 84108

Address correspondence to Wesley I. Sundquist, Dept. of Biochemistry, University of Utah, 20 N, 1900 E, Rm. 211, Salt Lake City, UT 84132. Tel.: (801) 595-8203. Fax: (801) 581-7959. email: wes{at}biochem.utah.edu

The HIV-1 Gag protein recruits the cellular factor Tsg101 to facilitate the final stages of virus budding. A conserved P(S/T)AP tetrapeptide motif within Gag (the "late domain") binds directly to the NH2-terminal ubiquitin E2 variant (UEV) domain of Tsg101. In the cell, Tsg101 is required for biogenesis of vesicles that bud into the lumen of late endosomal compartments called multivesicular bodies (MVBs). However, the mechanism by which Tsg101 is recruited from the cytoplasm onto the endosomal membrane has not been known. Now, we report that Tsg101 binds the COOH-terminal region of the endosomal protein hepatocyte growth factor–regulated tyrosine kinase substrate (Hrs; residues 222–777). This interaction is mediated, in part, by binding of the Tsg101 UEV domain to the Hrs 348PSAP351 motif. Importantly, Hrs222–777 can recruit Tsg101 and rescue the budding of virus-like Gag particles that are missing native late domains. These observations indicate that Hrs normally functions to recruit Tsg101 to the endosomal membrane. HIV-1 Gag apparently mimics this Hrs activity, and thereby usurps Tsg101 and other components of the MVB vesicle fission machinery to facilitate viral budding.

Key Words: virus budding; virions; ubiquitin; vacuolar protein sorting; multivesicular body

O. Pornillos, D.S. Higginson, and K.M. Stray contributed equally to this paper.

O. Pornillos' present address is The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037.

Abbreviations used in this paper: ESCRT, endosomal sorting complex required for transport; Hrs, hepatocyte growth factor–regulated tyrosine kinase substrate; MVB, multivesicular body; Tsg101, tumor susceptibility gene 101; UEV, ubiquitin E2 variant; UIM, ubiquitin-interacting motif; VLP, virus-like particle; Vps, vacuolar protein sorting.


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