title: HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation.
abstract: The human immunodeficiency virus (HIV) has been reported to target noninfected CD4 and CD8 cells for destruction. This effect is manifested in part through up-regulation of the death receptor Fas ligand (FasL) by HIV-1 negative factor (Nef), leading to bystander damage. However, the signal transduction and transcriptional regulation of this process remains elusive. Here, we provide evidence that p38 mitogen-activated protein kinase (MAPK) is required for this process. Loss-of-function experiments through dominant-negative p38 isoform, p38 siRNA, and chemical inhibitors of p38 activation suggest that p38 is necessary for Nef-induced activator protein-1 (AP-1) activation, as inhibition leads to an attenuation of AP-1-dependent transcription. Furthermore, mutagenesis of the FasL promoter reveals that its AP-1 enhancer element is required for Nef-mediated transcriptional activation. Therefore, a linear pathway for Nef-induced FasL expression that encompasses p38 and AP-1 has been elucidated. Furthermore, chemical inhibition of the p38 pathway attenuates HIV-1-mediated bystander killing of CD8 cells in vitro.
authors.affiliation: University of Pennsylvania School of Medicine, Department of Pathology & Laboratory Medicine 422 Curie Blvd, Philadelphia, PA 19104, USA.
authors.forename: Karuppiah
authors.initials: K
authors.lastname: Muthumani
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Choo
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Hwang
authors.forename: Arumugam
authors.initials: A
authors.lastname: Premkumar
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Dayes
authors.forename: Crafford
authors.initials: C
authors.lastname: Harris
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wadsworth
authors.forename: John J
authors.initials: JJ
authors.lastname: Siekierka
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D024201:Bystander Effect; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology* / Q000821:virology; D016923:Cell Death; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D015693:Gene Products, nef / Q000502:physiology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D018808:Transcription Factor AP-1; D015533:Transcriptional Activation; D054311:nef Gene Products, Human Immunodeficiency Virus; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015693:Gene Products, nef; D008562:Membrane Glycoproteins; D018808:Transcription Factor AP-1; D054311:nef Gene Products, Human Immunodeficiency Virus; D048051:p38 Mitogen-Activated Protein Kinases