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The G??-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation.

ABSTRACT: Formation of multi-component signaling complex necrosomes is essential for tumor necrosis factor ? (TNF)-induced programmed necrosis (also called necroptosis). However, the mechanisms of necroptosis are still largely unknown. We isolated a TNF-resistant L929 mutant cell line generated by retrovirus insertion and identified that disruption of the guanine nucleotide-binding protein ? 10 (G?10) gene is responsible for this phenotype. We further show that G?10 is involved in TNF-induced necroptosis and G?2 is the partner of G?10. Src is the downstream effector of G?2?10 in TNF-induced necroptosis because TNF-induced Src activation was impaired upon G?10 knockdown. G?10 does not affect TNF-induced activation of NF-?B and MAPKs and the formation of necrosomes, but is required for trafficking of necrosomes to their potential functioning site, an unidentified subcellular organelle that can be fractionated into heterotypic membrane fractions. The TNF-induced G??-Src signaling pathway is independent of RIP1/RIP3 kinase activity and necrosome formation, but is required for the necrosome to function.

SUBMITTER: Li L

PROVIDER: S-EPMC3975499 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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The Gβγ-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation.

Li Lisheng L Chen Wanze W Liang Yaoji Y Ma Huabin H Li Wenjuan W Zhou Zhenru Z Li Jie J Ding Yan Y Ren Junming J Lin Juan J Han Felicia F Wu Jianfeng J Han Jiahuai J

Cell research 20140211 4

Formation of multi-component signaling complex necrosomes is essential for tumor necrosis factor α (TNF)-induced programmed necrosis (also called necroptosis). However, the mechanisms of necroptosis are still largely unknown. We isolated a TNF-resistant L929 mutant cell line generated by retrovirus insertion and identified that disruption of the guanine nucleotide-binding protein γ 10 (Gγ10) gene is responsible for this phenotype. We further show that Gγ10 is involved in TNF-induced necroptosis ...[more]

PMID: 24513853

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Project description:Dysfunction of the intestinal epithelium is believed to result in the excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease, an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria adjacent to the epithelium. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn's disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death.

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The G??-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation.

Publications

The Gβγ-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation.

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