Autophagic programmed cell death by selective catalase degradation.
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.
Yu
Li
L
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
Wan
Fengyi
F
Dutta
Sudeshna
S
Welsh
Sarah
S
Liu
ZhiHua
Z
Freundt
Eric
E
Baehrecke
Eric H
EH
Lenardo
Michael
M
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D045744:Cell Line, Tumor; D051379:Mice; D046529:Microscopy, Electron, Transmission; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity
D000590:Amino Acid Chloromethyl Ketones; D017382:Reactive Oxygen Species; C476093:z-Val-Ala-Asp(Ome)-fluoromethylketone; D002374:Catalase; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases