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

Zhenyuan Tang, Yoshinori Takahashi, Chong Chen, Ying Liu, Haiyan He, Nikolaos Tsotakos, Jacob M. Serfass, Melat T. Gebru, Han Chen, Megan M. Young, Hong Gang Wang

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2127-2138
Number of pages12
JournalCell Death and Differentiation
Volume24
Issue number12
DOIs
StatePublished - Dec 1 2017

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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