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Journal of Virology, July 2003, p. 8116-8126, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.8116-8126.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cooperative Interactions of Simian Immunodeficiency Virus Nef, AP-2, and CD3-{zeta} Mediate the Selective Induction of T-Cell Receptor-CD3 Endocytosis

Tomek Swigut, Michael Greenberg,{dagger} and Jacek Skowronski*

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724

Received 18 December 2002/ Accepted 16 April 2003

The Nef proteins of human immunodeficiency virus and simian immunodeficiency virus (SIV) bind the AP-1 and AP-2 clathrin adaptors to downmodulate the expression of CD4 and CD28 by recruiting them to sites of AP-2 clathrin-dependent endocytosis. Additionally, SIV Nef directly binds the CD3-{zeta} subunit of the CD3 complex and downmodulates the T-cell receptor (TCR)-CD3 complex. We report here that SIV mac239 Nef induces the endocytosis of TCR-CD3 in Jurkat T cells. SIV Nef also induces the endocytosis of a chimeric CD8-CD3-{zeta} protein containing only the CD3-{zeta} cytoplasmic domain (8-{zeta}), in the absence of other CD3 subunits. Thus, the interaction of SIV Nef with CD3-{zeta} likely mediates the induction of TCR-CD3 endocytosis. In cells expressing SIV Nef and 8-{zeta}, both proteins colocalize with AP-2, indicating that Nef induces 8-{zeta} internalization via this pathway. Surprisingly, deletion of constitutively strong AP-2 binding determinants (CAIDs) in SIV Nef had little effect on its ability to induce TCR-CD3, or 8-{zeta} endocytosis, even though these determinants are required for the induction of CD4 and CD28 endocytosis via this pathway. Fluorescent microscopic analyses revealed that while neither the mutant SIV Nef protein nor 8-{zeta} colocalized with AP-2 when expressed independently, both proteins colocalized with AP-2 when coexpressed. In vitro binding studies using recombinant SIV Nef proteins lacking CAIDs and recombinant CD3-{zeta} cytoplasmic domain demonstrated that SIV Nef and CD3-{zeta} cooperate to bind AP-2 via a novel interaction. The fact that Nef uses distinct AP-2 interaction surfaces to recruit specific membrane receptors demonstrates how Nef independently selects distinct types of target receptors and recruits them to AP-2 for endocytosis.

* Corresponding author. Mailing address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. Phone: (516) 367-8407. Fax: (516) 367-8454. E-mail: skowrons{at}cshl.org.

{dagger} Present address: Cleveland Research Foundation, Lerner Research Institute, Cleveland, OH 44195.

Journal of Virology, July 2003, p. 8116-8126, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.8116-8126.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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