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MBC in Press, published online ahead of print December 24, 2008
Mol. Biol. Cell 10.1091/mbc.E08-08-0829

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Submitted on August 13, 2008
Revised on December 3, 2008
Accepted on December 8, 2008

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor Deprived Cells to Apoptosis

Brian J. Altman,* Jessica A. Wofford,* Yuxing Zhao,* Jonathan L. Coloff,* Emily C. Ferguson,* Heather L. Wieman,* Amanda E. Day,* Olga Ilkayeva,*{dagger} and Jeffrey C. Rathmell*{dagger}{ddagger}

*Department of Pharmacology and Cancer Biology, {dagger}Sarah W. Stedman Nutrition and Metabolism Center, {ddagger}Department of Immunology, Duke University Medical Center, Durham, NC, 27710

Monitoring Editor: Donald D. Newmeyer

Tissue homeostasis is controlled by the availability of growth factors, which sustain exogenous nutrient uptake and prevent apoptosis. While autophagy can provide an alternate intracellular nutrient source to support essential basal metabolism of apoptosis-resistant growth factor-withdrawn cells, anti-apoptotic Bcl-2 family proteins can suppress autophagy in some settings. Thus, the role of autophagy and interactions between autophagy and apoptosis in growth factor withdrawn cells expressing Bcl-2 or Bcl-xL were unclear. Here we show autophagy is rapidly induced in hematopoietic cells upon growth factor withdrawal regardless of Bcl-2 or Bcl-xL expression and led to increased mitochondrial lipid oxidation. Deficiency in autophagy-essential gene expression, however, did not lead to metabolic catastrophe and rapid death of growth factor-deprived cells. Rather, inhibition of autophagy enhanced survival of cells with moderate Bcl-2 expression for greater than one week, indicating that autophagy promoted cell death in this time frame. Cell death was not autophagic, but apoptotic, and relied on Chop-dependent induction of the proapoptotic Bcl-2 family protein Bim. Therefore, although ultimately important, autophagy-derived nutrients appear initially nonessential after growth factor withdrawal. Instead, autophagy promotes tissue homeostasis by sensitizing cells to apoptosis to ensure only the most apoptosis-resistant cells survive long-term using autophagy-derived nutrients when growth factor deprived.

Address correspondence to: Jeffrey C. Rathmell (rathm001{at}mc.duke.edu)




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