Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1

• 成果类型: Article
• 署名作者: Zhang, Tao; Xu, Daichao; Trefts, Elijah; Lv, Mingming; Inuzuka, Hiroyuki; Song, Guobin; Liu, Min; Lu, Jianlin; Liu, Jianping; Chu, Chen; Wang, Min; Wang, Huibing; Meng, Huyan; Liu, Hui; Zhuang, Yuan; Xie, Xingxing; Dang, Fabin; Guan, Dongxian; Men, Yuqin; Jiang, Shuwen; Jiang, Cong; Dai, Xiaoming; Liu, Jing; Wang, Zhen; Yan, Peiqiang; Wang, Jingchao; Tu, Zhenbo; Babuta, Mrigya; Erickson, Emily; Hillis, Alissandra L.; Dibble, Christian C.; Asara, John M.; Szabo, Gyongy; Sicinski, Piotr; Miao, Ji; Lee, Yu-Ru; Pan, Lifeng; Shaw, Reuben J.; Yuan, Junying; Wei, Wenyi
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; Harvard University; Harvard Medical School; Salk Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; St Jude Children's Research Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Huazhong University of Science & Technology; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Jinan University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Academia Sinica - Taiwan; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Shanghai Institute of Organic Chemistry, CAS
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-14099
• DOI: 10.1126/science.abn1725
• 发表日期: 2023-06-30
• 页码: 1372-1380
• 关键词: activated protein-kinase; mixed lineage kinase; receptor; gene; caspase-8; necrosis; identification; necroptosis; mechanisms; apoptosis

摘要

Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser(415) to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampk alpha 1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.