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Journal of Virology, January 2006, p. 108-118, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.108-118.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Association of Herpesvirus Saimiri Tip with Lipid Raft Is Essential for Downregulation of T-Cell Receptor and CD4 Coreceptor

Nam-Hyuk Cho,1,2* Dior Kingston,1 Heesoon Chang,1 Eun-Kyung Kwon,2 Jo-Min Kim,2 Jung Hee Lee,2 Hyuk Chu,2 Myung-Sik Choi,2 Ik-Sang Kim,2 and Jae Ung Jung1*

Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102,1 Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 110-799, South Korea2

Received 13 June 2005/ Accepted 4 October 2005

Lipid rafts are membrane microdomains that are proposed to function as platforms for both receptor signaling and trafficking. Our previous studies have demonstrated that Tip of herpesvirus saimiri (HVS), which is a T-lymphotropic tumor virus, is constitutively targeted to lipid rafts and interacts with cellular Lck tyrosine kinase and p80 WD repeat-containing endosomal protein. Through the interactions with Lck and p80, HVS Tip modulates diverse T-cell functions, which leads to the downregulation of T-cell receptor (TCR) and CD4 coreceptor surface expression, the inhibition of TCR signal transduction, and the activation of STAT3 transcription factor. In this study, we investigated the functional significance of Tip association with lipid rafts. We found that Tip expression remarkably increased lipid raft fractions in human T cells by enhancing the recruitment of lipid raft-resident proteins. Genetic analysis showed that the carboxyl-terminal transmembrane, but not p80 and Lck interaction, of Tip was required for the lipid raft localization and that lipid raft localization of Tip was necessary for the efficient downregulation of TCR and CD4 surface expression. Correlated with this, treatment with Filipin III, a lipid raft-disrupting agent, effectively reversed the downregulation of CD3 and CD4 surface expression induced by Tip. On the other hand, Tip mutants that were no longer present in lipid rafts were still capable of inhibiting TCR signaling and activating STAT3 transcription factor activity as efficiently as wild-type (wt) Tip. These results indicate that the association of Tip with lipid rafts is essential for the downregulation of TCR and CD4 surface expression but not for the inhibition of TCR signal transduction and the activation of STAT3 transcription factor. These results also suggest that the signaling and targeting activities of HVS Tip rely on functionally and genetically separable mechanisms, which may independently modulate T-cell function for viral persistence or pathogenesis.

* Corresponding author. Mailing address for Nam-Hyuk Cho: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 110-799, South Korea. Phone: 82-2-740-8392. Fax: 82-2-743-0881. E-mail: chonh{at}snu.ac.kr. Mailing address for Jae Jung: Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, MA 01772-9102. Phone: (508) 624-8083. Fax: (508) 786-1416. E-mail: jae_jung{at}hms.harvard.edu.

Journal of Virology, January 2006, p. 108-118, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.108-118.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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