期刊
JOURNAL OF CELL SCIENCE
卷 125, 期 12, 页码 2995-3003出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.103093
关键词
TNF; STAT3; GRIM-19; Necroptosis; Mitochondria
类别
资金
- National Cancer Institute [5R01AA012897-11]
- National Institute of Alcohol Abuse and Alcoholism [5R01CA118356-07]
Tumor necrosis factor (TNF) can induce necroptosis, wherein inhibition of caspase activity prevents apoptosis but initiates an alternative programmed necrosis. The activity of receptor-interacting serine/threonine-protein kinase 1 (RIPK-1) is required for necroptosis to proceed, with suppression of RIPK-1 expression or inhibition of RIPK-1 activity with necrostatin-1 preventing TNF-induced necroptosis. Downstream from the TNF receptor, the generation of reactive oxygen species at the mitochondria has been identified as necessary for the execution of necroptosis; with antioxidants and inhibitors of mitochondrial complex I preventing TNF-induced cytotoxicity. However, components of the signaling pathway that lie between activated RIPK-1 and the mitochondria are unknown. In the study reported here we demonstrate that during TNF-induced necroptosis, STAT3 is phosphorylated on serine 727, which is dependent on RIPK-1 expression or activity. The phosphorylation of STAT3 induces interaction with GRIM-19, a subunit of mitochondrial complex I, with a resultant translocation of STAT3 to the mitochondria, where it induces an increase in reactive oxygen species production and cell death.
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