HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation.
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.
Muthumani
Karuppiah
K
University of Pennsylvania School of Medicine, Department of Pathology & Laboratory Medicine 422 Curie Blvd, Philadelphia, PA 19104, USA.
Choo
Andrew Y
AY
Hwang
Daniel S
DS
Premkumar
Arumugam
A
Dayes
Nathanael S
NS
Harris
Crafford
C
Green
Douglas R
DR
Wadsworth
Scott A
SA
Siekierka
John J
JJ
Weiner
David B
DB
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*
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