组织蛋白酶B
细胞生物学
自噬
溶酶体
程序性细胞死亡
生物
细胞器
DNA损伤
化学
细胞凋亡
DNA
生物化学
酶
作者
Feimei Kuang,Jiao Liu,Changfeng Li,Rui Kang,Daolin Tang
标识
DOI:10.1016/j.bbrc.2020.10.035
摘要
Ferroptosis is a type of non-apoptotic regulated cell death that involves excessive iron accumulation and subsequent lipid peroxidation. Although the antioxidant mechanisms of ferroptosis have been extensively studied recently, little is known about the interactions between the different organelles that control ferroptosis. Here, we show that the translocation of lysosomal cysteine protease cathepsin B (CTSB) into the nucleus is an important molecular event that mediates organelle-specific initiation of ferroptosis in human pancreatic cancer cells. Iron-dependent lysosomal membrane permeability triggers the release of CTSB from the lysosome to nucleus during ferroptosis. Mechanistically, nuclear CTSB accumulation causes DNA damage and subsequent activation of the stimulator of interferon response CGAMP interactor 1 (STING1/STING)-dependent DNA sensor pathway, which ultimately leads to autophagy-dependent ferroptosis. Consequently, the genetic inhibition of CTSB-dependent STING1 activation by RNAi prevents ferroptosis in cell culture and animal models. These new findings not only enhance our understanding of the mechanism by which organelles specifically trigger ferroptosis, but also may provide a potential way to enhance the anticancer activity of ferroptosis therapy.
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