期刊
CELLS
卷 11, 期 19, 页码 -出版社
MDPI
DOI: 10.3390/cells11193053
关键词
caspase-9-independent cell death; Erk1; Alox5; ROS; lipid peroxidation
类别
资金
- US NIH [R01GM087710, R01AI123221, R01DK083164]
- United States Department of Defense [PR190958]
- Cytometry and Cell Sorting Core at Baylor College of Medicine
- Methodist Hospital Research Institute
- NIH [P30 AI036211, P30 CA125123, S10 RR024574]
Mitochondrial disruption can lead to cell death through caspase-9 activation. However, cell death can also occur independently of caspase-9, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, researchers identified a network of genes that mediate caspase-9-independent cell death through ROS production and Alox5-dependent membrane lipid peroxidation. The Erk1-Alox5 pathway plays a critical role in promoting membrane lipid peroxidation and nuclear translocation of cytolytic molecules, resulting in cell death.
Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade.
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