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TitleRIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.
Journal, issue, pagesCell Metab, Vol. 37, Issue 8, Page 1732-11749.e9, Year 2025
Publish dateAug 5, 2025
AuthorsZezhao Chen / Xiaosong Gu / Hongbo Chen / Huijing Zhang / Jianping Liu / Xiaohua Yang / Yuping Cai / Mengmeng Zhang / Lingjie Yan / Yuanxin Yang / Bing Shan / Zheng-Jiang Zhu / Yixiao Zhang / Jinyang Gu / Daichao Xu /
PubMed AbstractThe capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient ...The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S-adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.
External linksCell Metab / PubMed:40570842
MethodsEM (helical sym.)
Resolution3.02 Å
Structure data

62587

9kv7

EMDB-62587, PDB-9kv7:
Cryo-EM structure of mouse RIPK1-DD filament
Method: EM (helical sym.) / Resolution: 3.02 Å

Source
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / RIPK1 / death domain / 568-656 / dimerization

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