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

1. Science. 2023 Jun 30;380(6652):1372-1380. doi: 10.1126/science.abn1725. Epub 2023 Jun 29.

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

Zhang T(#)(1), Xu D(#)(2)(3), Trefts E(#)(4), Lv M(#)(1), Inuzuka H(1), Song G(5), Liu M(6), Lu J(7), Liu J(2), Chu C(8)(9), Wang M(10), Wang H(3), Meng H(11), Liu H(1), Zhuang Y(12), Xie X(2), Dang F(1), Guan D(5), Men Y(5), Jiang S(5)(13), Jiang C(1), Dai X(1), Liu J(1), Wang Z(1), Yan P(1), Wang J(1), Tu Z(1), Babuta M(12), Erickson E(1), Hillis AL(1), Dibble CC(1), Asara JM(14), Szabo G(12), Sicinski P(8)(9)(15), Miao J(5), Lee YR(16), Pan L(17), Shaw RJ(4), Yuan J(2)(3), Wei W(1).

Author information: (1)Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. (2)Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China. (3)Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. (4)The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. (5)Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA. (6)Transfusion Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA. (7)Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA. (8)Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9)Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. (10)Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China. (11)F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA. (12)Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. (13)Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, 510632 Guangzhou, China. (14)Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. (15)Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland. (16)Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan. (17)State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200032 Shanghai, China. (#)Contributed equally

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 Ser415 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 Ampkα1-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.

DOI: 10.1126/science.abn1725 PMCID: PMC10617018 PMID: 37384704 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: W.W. is a cofounder and consultant for ReKindle Therapeutics. P.S. has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, Cedilla Therapeutics, Syros Pharmaceuticals, Exo Therapeutics, Curie Bio Operations, Exscientia, Ligature Therapeutics, and Redesign Science; and his laboratory receives research funding from Novartis. G.Sz. is a paid consultant for Cyta Therapeutics, Durect Co, Evive, Merck, Pfizer, Surrozen, Terra Firma, Pandion Therapeutics, LabCorp, Glympse Bio, Satellite Bio, and Zomagen. G.Sz. has additional financial interests in Glympse Bio, Satellite Bio, and Zomagen. The other authors declare that they have no competing financial interests.