HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation

Karuppiah Muthumani, Andrew Y. Choo, Daniel S. Hwang, Arumugam Premkumar, Nathanael S. Dayes, Crafford Harris, Douglas R. Green, Scott A. Wadsworth, John Siekierka, David B. Weiner

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36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2059-2068
Number of pages10
JournalBlood
Volume106
Issue number6
DOIs
StatePublished - 15 Sep 2005

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Fas Ligand Protein
Transcription Factor AP-1
p38 Mitogen-Activated Protein Kinases
HIV-1
Death Domain Receptors
Mutagenesis
Transcriptional Activation
Signal Transduction
Protein Isoforms
Up-Regulation
HIV

Cite this

Muthumani, K., Choo, A. Y., Hwang, D. S., Premkumar, A., Dayes, N. S., Harris, C., ... Weiner, D. B. (2005). HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Blood, 106(6), 2059-2068. https://doi.org/10.1182/blood-2005-03-0932
Muthumani, Karuppiah ; Choo, Andrew Y. ; Hwang, Daniel S. ; Premkumar, Arumugam ; Dayes, Nathanael S. ; Harris, Crafford ; Green, Douglas R. ; Wadsworth, Scott A. ; Siekierka, John ; Weiner, David B. / HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. In: Blood. 2005 ; Vol. 106, No. 6. pp. 2059-2068.
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abstract = "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.",
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Muthumani, K, Choo, AY, Hwang, DS, Premkumar, A, Dayes, NS, Harris, C, Green, DR, Wadsworth, SA, Siekierka, J & Weiner, DB 2005, 'HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation', Blood, vol. 106, no. 6, pp. 2059-2068. https://doi.org/10.1182/blood-2005-03-0932

HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. / Muthumani, Karuppiah; Choo, Andrew Y.; Hwang, Daniel S.; Premkumar, Arumugam; Dayes, Nathanael S.; Harris, Crafford; Green, Douglas R.; Wadsworth, Scott A.; Siekierka, John; Weiner, David B.

In: Blood, Vol. 106, No. 6, 15.09.2005, p. 2059-2068.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Dayes, Nathanael S.

AU - Harris, Crafford

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AU - Siekierka, John

AU - Weiner, David B.

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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.

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Muthumani K, Choo AY, Hwang DS, Premkumar A, Dayes NS, Harris C et al. HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Blood. 2005 Sep 15;106(6):2059-2068. https://doi.org/10.1182/blood-2005-03-0932