title: Signaling pathways from membrane lipid rafts to JNK1 activation in reactive nitrogen species-induced non-apoptotic cell death.
abstract: At present, the signaling pathways controlling reactive nitrogen species (RNS)-induced non-apoptotic cell death are relatively less understood. In this work, various RNS donors are found to induce caspase-independent non-apoptotic cell death in mouse embryonic fibroblasts (MEF). In search of the molecular mechanisms, we first established the role of c-Jun N-terminal kinase (JNK) in RNS-induced non-apoptotic cell death. RNS readily activate JNK, and the jnk1-/- MEF are resistant to RNS-induced cell death. Moreover, the reconstitution of JNK1 effectively restores the sensitivity to RNS. Next, we identified tumor necrosis factor receptor-associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) as the essential upstream molecules for RNS-induced JNK activation and cell death. RNS fail to activate JNK and induce cell death in traf2-/- MEF; and reconstitution of TRAF2 effectively restores the responsiveness of traf2-/- MEF to RNS. Moreover, RNS-induced ASK1 activation is impaired in traf2-/- cells and overexpression of a mutant ASK1 protein suppresses RNS-induced cell death in wild-type MEF cells. Last, we explored the signaling events upstream of TRAF2 and found that translocation of TRAF2 and JNK1 onto membrane lipid rafts is required for RNS-mediated JNK1 activation and cell death. Taken together, data from our study reveal a novel signaling pathway regulating RNS-induced JNK1 activation and non-apoptotic cell death.
authors.affiliation: Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.forename: Y-S
authors.initials: YS
authors.lastname: Kim
authors.forename: H-L
authors.initials: HL
authors.lastname: Tan
authors.forename: M
authors.initials: M
authors.lastname: Whiteman
authors.forename: C-N
authors.initials: CN
authors.lastname: Ong
authors.forename: Z-G
authors.initials: ZG
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Ichijo
authors.forename: H-M
authors.initials: HM
authors.lastname: Shen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011500:Protein Synthesis Inhibitors; D026361:Reactive Nitrogen Species; C499176:T2bp protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D048670:MAP Kinase Kinase 4