TY - JOUR
T1 - HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation
AU - Muthumani, Karuppiah
AU - Choo, Andrew Y.
AU - Hwang, Daniel S.
AU - Premkumar, Arumugam
AU - Dayes, Nathanael S.
AU - Harris, Crafford
AU - Green, Douglas R.
AU - Wadsworth, Scott A.
AU - Siekierka, John J.
AU - Weiner, David B.
PY - 2005/9/15
Y1 - 2005/9/15
N2 - The human immunodeficiency virus (HIV) has been reported to target non infected CD4 and CD8 cells for destruction. This effect is manifested in part through upregulation 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.
AB - The human immunodeficiency virus (HIV) has been reported to target non infected CD4 and CD8 cells for destruction. This effect is manifested in part through upregulation 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.
UR - http://www.scopus.com/inward/record.url?scp=24744438912&partnerID=8YFLogxK
U2 - 10.1182/blood-2005-03-0932
DO - 10.1182/blood-2005-03-0932
M3 - Article
C2 - 15928037
AN - SCOPUS:24744438912
SN - 0006-4971
VL - 106
SP - 2059
EP - 2068
JO - Blood
JF - Blood
IS - 6
ER -