title: HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1α, JNK and AP-1 pathway.
abstract: The ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases; however, its role in HIV/neuroAIDS remains largely unexplored. The present study was undertaken to assess the involvement and detailed mechanism of IRE1α pathway in HIV-1 gp120-mediated ER stress and its possible involvement in cell death. Various signaling molecules for IRE1α pathway were assessed using SVGA cells, primary astrocytes and gp120 transgenic mice, which demonstrated gp120-mediated increase in phosphorylated JNK, XBP-1 and AP-1 leading to upregulation of CHOP. Furthermore, HIV-1 gp120-mediated activation of IRE1α also increased XBP-1 splicing. The functional consequence of gp120-mediated ER stress was determined via assessment of gp120-mediated cell death using PI staining and MTT assay. The gp120-mediated cell death also involved caspase-9/caspase-3-mediated apoptosis. These findings were confirmed with the help of specific siRNA for IRE1α, JNK, AP-1, BiP and CHOP showing significant reduction in gp120-mediated CHOP expression. Additionally, silencing all the intermediates also reduced the gp120-mediated cell death and caspase-9/caspase-3 activation at differential levels. This study provides ER-stress as a novel therapeutic target in the management of gp120-mediated cell death and possibly in the treatment of neuroAIDS.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, Kansas City, MO 64108.
authors.forename: Ankit
authors.initials: A
authors.lastname: Shah
authors.affiliation: Department of Mathematics and Statistics, University of Missouri-Kansas City, Kansas City, MO 64108.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Vaidya
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, Kansas City, MO 64108.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, Kansas City, MO 64108.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000502:physiology; D001483:Base Sequence; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012326:RNA Splicing; D034741:RNA, Small Interfering / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: C497249:DDIT3 protein, human; D015699:HIV Envelope Protein gp120; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C514793:gp120 protein, Human immunodeficiency virus 1; D051742:Transcription Factor CHOP; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases