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J. Biol. Chem., Vol. 283, Issue 8, 4766-4777, February 22, 2008

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Loss of Macroautophagy Promotes or Prevents Fibroblast Apoptosis Depending on the Death Stimulus^*

Yongjun Wang¹, Rajat Singh¹, Ashish C. Massey^¶, Saul S. Kane, Susmita Kaushik^¶, Taneisha Grant, Youqing Xiang, Ana Maria Cuervo^¶, and Mark J. Czaja²

From the Departments of Medicine and ^¶Anatomy and Structural Biology and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, 10461

Macroautophagy has been implicated as a mechanism of cell death. However, the relationship between this degradative pathway and cell death is unclear as macroautophagy has been shown recently to protect against apoptosis. To better define the interplay between these two critical cellular processes, we determined whether inhibition of macroautophagy could have both pro-apoptotic and anti-apoptotic effects in the same cell. Embryonic fibroblasts from mice with a knock-out of the essential macroautophagy gene atg5 were treated with activators of the extrinsic and intrinsic death pathways. Loss of macroautophagy sensitized these cells to caspase-dependent apoptosis from the death receptor ligands Fas and tumor necrosis factor- (TNF-). Atg5^-/- mouse embryonic fibroblasts had increased activation of the mitochondrial death pathway in response to Fas/TNF- in concert with decreased ATP levels. Fas/TNF- treatment failed to up-regulate macroautophagy, and in fact, decreased activity at late time points. In contrast to their sensitization to Fas/TNF-, Atg5^-/- cells were resistant to death from menadione and UV light. In the absence of macroautophagy, an up-regulation of chaperone-mediated autophagy induced resistance to these stressors. These results demonstrate that inhibition of macroautophagy can promote or prevent apoptosis in the same cell and that the response is governed by the nature of the death stimulus and compensatory changes in other forms of autophagy. Experimental findings that an inhibition of macroautophagy blocks apoptosis do not prove that autophagy mediates cell death as this effect may result from the protective up-regulation of other autophagic pathways such as chaperone-mediated autophagy.

Received for publication, August 10, 2007 , and in revised form, December 6, 2007.

^* This work was supported by National Institutes of Health Grants AG021904 and DK041918 (to A. M. C.), DK044234 (to M. J. C.), and T32AG023475 (to A. C. M.) and an American Liver Foundation Postdoctoral Research Fellowship Award (to R. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains four supplemental figures.

This article was selected as a Paper of the Week.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-4255; Fax: 718-430-8975; E-mail: czaja{at}aecom.yu.edu.

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