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J. Biol. Chem., Vol. 279, Issue 34, 36059-36071, August 20, 2004

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The Human Endosomal Sorting Complex Required for Transport (ESCRT-I) and Its Role in HIV-1 Budding^*

Melissa D. Stuchell, Jennifer E. Garrus¶, Barbara Müller||, Kirsten M. Stray, Sanaz Ghaffarian, Rena McKinnon¶, Hans-Georg Kräusslich||, Scott G. Morham**, and Wesley I. Sundquist

From the Department of Biochemistry, University of Utah, Salt Lake City, Utah 84132-3201, the ^||Abteilung Virologie, Universitätsklinikum Heidelberg, D-69120 Heidelberg, Germany, and ^**Myriad Genetics, Incorporated, Salt Lake City, Utah 84108

Efficient human immunodeficiency virus type 1 (HIV-1) budding requires an interaction between the PTAP late domain in the viral p6^Gag protein and the cellular protein TSG101. In yeast, Vps23p/TSG101 binds both Vps28p and Vps37p to form the soluble ESCRT-I complex, which functions in sorting ubiquitylated protein cargoes into multivesicular bodies. Human cells also contain ESCRT-I, but the VPS37 component(s) have not been identified. Bioinformatics and yeast two-hybrid screening methods were therefore used to identify four novel human proteins (VPS37A–D) that share weak but significant sequence similarity with yeast Vps37p and to demonstrate that VPS37A and VPS37B bind TSG101. Detailed studies produced four lines of evidence that human VPS37B is a Vps37p ortholog. 1) TSG101 bound to several different sites on VPS37B, including a putative coiled-coil region and a PTAP motif. 2) TSG101 and VPS28 co-immunoprecipitated with VPS37B-FLAG, and the three proteins comigrated together in soluble complexes of the correct size for human ESCRT-I (350 kDa). 3) Like TGS101, VPS37B became trapped on aberrant endosomal compartments in the presence of VPS4A proteins lacking ATPase activity. 4) Finally, VPS37B could recruit TSG101/ESCRT-I activity and thereby rescue the budding of both mutant Gag particles and HIV-1 viruses lacking native late domains. Further studies of ESCRT-I revealed that TSG101 mutations that inhibited PTAP or VPS28 binding blocked HIV-1 budding. Taken together, these experiments define new components of the human ESCRT-I complex and characterize several TSG101 protein/protein interactions required for HIV-1 budding and infectivity.

Received for publication, May 11, 2004 , and in revised form, June 15, 2004.

^* This work was supported by a National Institutes of Health Grant R01 AI51174 (to W. I. S.) and Deutsche Forschungsgemeinschaft Grant SFB638 (to H.-G. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental "Results" and Supplemental Fig. 1.

Both authors contributed equally to this work.

^¶ Present address: Myriad Genetics, Inc., Salt Lake City, UT 84108.

To whom correspondence should be addressed: Dept. of Biochemistry, University of Utah School of Medicine, 20 N, 1900 E, Salt Lake City, UT 84132-3201. Tel.: 801-585-5402; Fax: 801-581-7959; E-mail: wes{at}biochem.utah.edu.

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