Autophagic programmed cell death by selective catalase degradation

doi:10.1073/pnas.0511288103

Autophagic programmed cell death by selective catalase degradation

*Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852;
^†Center for Biosystems Research, University of Maryland Biotechnology Institute, College Park, MD 20742;
^‡Harvard Center for Neurodegeneration and Repair and Department of Neurology, Harvard Medical School, Boston, MA 02115; and
^§Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, United Kingdom

Communicated by Jacques F. A. P. Miller, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, December 29, 2005 (received for review November 1, 2005)

Abstract

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.

Footnotes

^¶To whom correspondence should be addressed. E-mail: lenardo{at}nih.gov
Author contributions: L.Y., F.W., E.H.B., and M.L. designed research; L.Y., F.W., S.D., S.W., Z.L., and E.F. performed research; L.Y. contributed new reagents/analytic tools; L.Y., E.H.B., and M.L. analyzed data; and L.Y., F.W., E.H.B., and M.L. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

ROS,

reactive oxygen species;

SOD,

superoxide dismutase;

zVAD,

benzyloxycarbonyl-valyl-alanyl-aspartic-acid (O-methyl)-fluoromethylketone;

RNAi,

RNA interference;

PG,

propyl gallate;

OG,

octyl gallate;

NDGA,

nordihydroguaiaretic acid;

TBHQ,

tert-butylhydroquinone;

Ionox 100,

2,6-di-tert-butyl-4-hydroxymethyl-phenol;

BHA,

butylated hydroxyanisole;

Pep A,

pepstatin A;

LC3,

light chain 3;

RIP,

receptor interacting protein;

JNK,

c-Jun N-terminal kinase;

LDH,

lactate dehydrogenase;

LOOH,

lipid hydroperoxide;

DCF,

dichlorodihydrofluorescein diacetate.