In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 4 ( 2021-4-26), p. e3001134-
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001134
DOI:
10.1371/journal.pbio.3001134.g001
DOI:
10.1371/journal.pbio.3001134.g002
DOI:
10.1371/journal.pbio.3001134.g003
DOI:
10.1371/journal.pbio.3001134.g004
DOI:
10.1371/journal.pbio.3001134.g005
DOI:
10.1371/journal.pbio.3001134.g006
DOI:
10.1371/journal.pbio.3001134.g007
DOI:
10.1371/journal.pbio.3001134.s001
DOI:
10.1371/journal.pbio.3001134.s002
DOI:
10.1371/journal.pbio.3001134.s003
DOI:
10.1371/journal.pbio.3001134.s004
DOI:
10.1371/journal.pbio.3001134.s005
DOI:
10.1371/journal.pbio.3001134.s006
DOI:
10.1371/journal.pbio.3001134.s007
DOI:
10.1371/journal.pbio.3001134.s008
DOI:
10.1371/journal.pbio.3001134.s009
DOI:
10.1371/journal.pbio.3001134.s010
DOI:
10.1371/journal.pbio.3001134.s011
DOI:
10.1371/journal.pbio.3001134.s012
DOI:
10.1371/journal.pbio.3001134.s013
DOI:
10.1371/journal.pbio.3001134.s014
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
