Farnesyl pyrophosphate is a new danger signal inducing acute cell death

Jing Chen, Xiaochen Zhang, Liping Li, Xianqiang Ma, Chunxiao Yang, Zhaodi Liu, Chenyang Li, Maria J. Fernandez-Cabezudo, Basel K. al-Ramadi, Chuan Wu, Weishan Huang, Yong Zhang, Yonghui Zhang, Wanli Liu

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Cell death is a vital event in life. Infections and injuries cause lytic cell death, which gives rise to danger signals that can further induce cell death, inflammation, and tissue damage. The mevalonate (MVA) pathway is an essential, highly conserved and dynamic metabolic pathway. Here, we discover that farnesyl pyrophosphate (FPP), a metabolic intermediate of the MVA pathway, functions as a newly identified danger signal to trigger acute cell death leading to neuron loss in stroke. Harboring both a hydrophobic 15-carbon isoprenyl chain and a heavily charged pyrophosphate head, FPP leads to acute cell death independent of its downstream metabolic pathways. Mechanistically, extracellular calcium influx and the cation channel transient receptor potential melastatin 2 (TRPM2) exhibit essential roles in FPP-induced cell death. FPP activates TRPM2 opening for ion influx. Furthermore, in terms of a mouse model constructing by middle cerebral artery occlusion (MCAO), FPP accumulates in the brain, which indicates the function of the FPP and TRPM2 danger signal axis in ischemic injury. Overall, our data have revealed a novel function of the MVA pathway intermediate metabolite FPP as a danger signal via transient receptor potential cation channels.

Original languageEnglish
Article numbere3001134
JournalPLoS Biology
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 2021

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Agricultural and Biological Sciences

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