title: Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain.
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.
authors.affiliation: Medical Research Council Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
authors.forename: X N
authors.initials: XN
authors.lastname: Xu
authors.forename: B
authors.initials: B
authors.lastname: Laffert
authors.forename: G R
authors.initials: GR
authors.lastname: Screaton
authors.forename: M
authors.initials: M
authors.lastname: Kraft
authors.forename: D
authors.initials: D
authors.lastname: Wolf
authors.forename: W
authors.initials: W
authors.lastname: Kolanus
authors.forename: J
authors.initials: J
authors.lastname: Mongkolsapay
authors.forename: A J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: A S
authors.initials: AS
authors.lastname: Baur
mesh_terms: D053222:Fas Ligand Protein; D015693:Gene Products, nef / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015854:Up-Regulation; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015693:Gene Products, nef; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D054311:nef Gene Products, Human Immunodeficiency Virus; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases