Journal
AUTOPHAGY
Volume 7, Issue 10, Pages 1173-1186Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.7.10.16681
Keywords
mTOR; TSC2; autophagy; starvation; hypoxia; apoptosis
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Funding
- Singapore Biomedical Research Council [BMRC/08/1/21/19/554]
- NUS
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It has been well documented that cells deficient in either TSC1 or TSC2 are highly sensitive to various cell death stimuli. In this study, we utilized the TSC2(-/-) mouse embryonic fibroblasts (MEFs) to study the involvement of autophagy in the enhanced susceptibility of TSC2-null cells to cell death. We first confirmed that both TSC1-null and TSC2-null MEFs are more sensitive to apoptosis in response to amino acid starvation (EBSS) and hypoxia. Second, we found that both the basal and inducible autophagy in TSC2(-/-) MEFs is impaired, mainly due to constitutive activation of mTORC1. Third, suppression of autophagy by chloroquine and Atg7 knockdown sensitizes TSC2(+/+) cells, but not TSC2(-/-) cells, to EBSS induced cell death. Conversely, the inhibition of mTORC1 by raptor knockdown and rapamycin activates autophagy and subsequently rescues TSC2(-/-) cells. Finally, in starved cells, nutrient supplementations (insulin-like growth factor-1 (IGF-1) and leucine) enhanced cell death in TSC2(-/-) cells, but reduced cell death in TSC2(+/+) cells. Taken together, these data indicate that constitutive activation of mTORC1 in TSC2(-/-) cells leads to suppression of autophagy and enhanced susceptibility to stress-mediated cell death. Our findings thus provide new insights into the complex relationships among mTOR, autophagy and cell death, and support the possible autophagy-targeted intervention strategies for the treatment of TSC-related pathologies.
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