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

作者：Yongjun Wang, Rajat Singh, Ashish C. Massey, Saul S. Kane, Susmita Kaushik, Taneisha Grant, Youqing Xiang, Ana María Cuervo, Mark J. Czaja · 发表于：Journal of Biological Chemistry · 年份：2007 · DOI：10.1074/jbc.m706666200 · 被引用次数：133 · 研究领域：Autophagy in Disease and Therapy、Cell death mechanisms and regulation、Toxoplasma gondii Research Studies

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-alpha (TNF-alpha). Atg5-/- mouse embryonic fibroblasts had increased activation of the mitochondrial death pathway in response to Fas/TNF-alpha in concert with decreased ATP levels. Fas/TNF-alpha treatment failed to up-regulate macroautophagy, and in fact, decreased activity at late time points. In contrast to their sensitization to Fas/TNF-alpha, 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 autoph...