1. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain.
- Author
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Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, and Baur AS
- Subjects
- Fas Ligand Protein, HIV-1 physiology, Humans, Jurkat Cells, Protein Kinases metabolism, Protein Serine-Threonine Kinases metabolism, Up-Regulation, nef Gene Products, Human Immunodeficiency Virus, p21-Activated Kinases, Gene Products, nef metabolism, HIV-1 metabolism, Membrane Glycoproteins biosynthesis, Membrane Proteins metabolism, Receptors, Antigen, T-Cell metabolism
- Abstract
During HIV/SIV infection, there is widespread programmed cell death in infected and, perhaps more importantly, uninfected cells. Much of this apoptosis is mediated by Fas-Fas ligand (FasL) interactions. Previously we demonstrated in macaques that induction of FasL expression and apoptotic cell death of both CD4(+) and CD8(+) T cells by SIV is dependent on a functional nef gene. However, the molecular mechanism whereby HIV-1 induces the expression of FasL remained poorly understood. Here we report a direct association of HIV-1 Nef with the zeta chain of the T cell receptor (TCR) complex and the requirement of both proteins for HIV-mediated upregulation of FasL. Expression of FasL through Nef depended upon the integrity of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR zeta chain. Conformation for the importance of zeta for Nef-mediated signaling in T cells came from an independent finding. A single ITAM motif of zeta but not CD3epsilon was both required and sufficient to promote activation and binding of the Nef-associated kinase (NAK/p62). Our data imply that Nef can form a signaling complex with the TCR, which bypasses the requirement of antigen to initiate T cell activation and subsequently upregulation of FasL expression. Thus, our study may provide critical insights into the molecular mechanism whereby the HIV-1 accessory protein Nef contributes to the pathogenesis of HIV.
- Published
- 1999
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