2. Academic Validation
  3. Farnesyl pyrophosphate is a new danger signal inducing acute cell death

Farnesyl pyrophosphate is a new danger signal inducing acute cell death

  • PLoS Biol. 2021 Apr 26;19(4):e3001134. doi: 10.1371/journal.pbio.3001134.
Jing Chen 1,  Xiaochen Zhang 2,  Liping Li 3,  Xianqiang Ma 3,  Chunxiao Yang 4,  Zhaodi Liu 2,  Chenyang Li 2,  Maria J Fernandez-Cabezudo 5,  Basel K Al-Ramadi 6 7,  Chuan Wu 8,  Weishan Huang 9,  Yong Zhang 2,  Yonghui Zhang 3,  Wanli Liu 1 10
Affiliations

Affiliations

  • 1 School of Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.
  • 2 Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of People's Republic of China, IDG/McGovern Institute for Brain Research at Peking University, Beijing, China.
  • 3 Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing Advanced Innovation Center for Human Brain Protection, Beijing, China.
  • 4 School of Medicine, Nankai University, Tianjin, China.
  • 5 Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
  • 6 Department of Medical Microbiology & Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
  • 7 Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
  • 8 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • 9 Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
  • 10 Tsinghua-Peking Center for Life Sciences, Beijing, China.
PMID: 33901180 DOI: 10.1371/journal.pbio.3001134
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.

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