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Atg2A/B deficiency switches cytoprotective autophagy to non-canonical caspase-8 activation and apoptosis.


ABSTRACT: Autophagosomal membranes are emerging as platforms for various cell survival and death signaling networks beyond autophagy. While autophagy-dependent cell death has been reported in response to a variety of stimuli, the underlying molecular mechanisms remain far from clear. Here, we demonstrate that inhibition of autophagosome completion by Atg2A/B deletion accumulates immature autophagosomal membranes that promote non-canonical caspase-8 activation in response to nutrient starvation via an intracellular death-inducing signaling complex (iDISC). Importantly, iDISC-induced caspase-8 dimerization and activation occurs on accumulated autophagosomal membranes and requires the LC3 conjugation machinery but is independent from the extrinsic pathway of apoptosis. Moreover, we have identified NF-?B signaling and c-FLIP as negative regulators of iDISC-mediated caspase-8 activation and apoptosis. Collectively, these findings reveal autophagosomal membrane completion as a novel target to switch cytoprotective autophagy to apoptosis.

SUBMITTER: Tang Z 

PROVIDER: S-EPMC5686350 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Atg2A/B deficiency switches cytoprotective autophagy to non-canonical caspase-8 activation and apoptosis.

Tang Zhenyuan Z   Takahashi Yoshinori Y   Chen Chong C   Liu Ying Y   He Haiyan H   Tsotakos Nikolaos N   Serfass Jacob M JM   Gebru Melat T MT   Chen Han H   Young Megan M MM   Wang Hong-Gang HG  

Cell death and differentiation 20170811 12


Autophagosomal membranes are emerging as platforms for various cell survival and death signaling networks beyond autophagy. While autophagy-dependent cell death has been reported in response to a variety of stimuli, the underlying molecular mechanisms remain far from clear. Here, we demonstrate that inhibition of autophagosome completion by Atg2A/B deletion accumulates immature autophagosomal membranes that promote non-canonical caspase-8 activation in response to nutrient starvation via an intr  ...[more]

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