Autophagic programmed cell death by selective catalase degradation

被引:565
作者
Yu, L
Wan, FY
Dutta, S
Welsh, S
Liu, ZH
Freundt, E
Baehrecke, EH
Lenardo, M [1 ]
机构
[1] NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA
[2] Univ Maryland, Inst Biotechnol, Ctr Biosyst Res, College Pk, MD 20742 USA
[3] Harvard Univ, Sch Med, Harvard Ctr Neurodegenerat & Repair, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA
[5] Univ Oxford, Weatherall Inst Mol Med, Oxford OX3 9DS, England
关键词
apoptosis; necrosis; nonapoptotic; reactive oxygen species;
D O I
10.1073/pnas.0511288103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Autophagy plays a central role in regulating important cellular functions such as cell survival during starvation and control of infectious pathogens. Recently, it has been shown that autophagy can induce cells to die; however, the mechanism of the autophagic cell death program is unclear. We now show that caspase inhibition leading to cell death by means of autophagy involves reactive oxygen species (ROS) accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Inhibition of autophagy by chemical compounds or knocking down the expression of key autophagy proteins such as ATG7, ATG8, and receptor interacting protein (RIP) blocks ROS accumulation and cell death. The cause of abnormal ROS accumulation is the selective autophagic degradation of the major enzymatic ROS scavenger, catalase. Caspase inhibition directly induces catalase degradation and ROS accumulation, which can be blocked by autophagy inhibitors. These findings unveil a molecular mechanism for the role of autophagy in cell death and provide insight into the complex relationship between ROS and nonapoptotic programmed cell death.
引用
收藏
页码:4952 / 4957
页数:6
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