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

Cell Death Differ. 2017 Dec;24(12):2127-2138. doi: 10.1038/cdd.2017.133. Epub 2017 Aug 11.


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-κB 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.

MeSH terms

  • Apoptosis / physiology
  • Autophagosomes / metabolism
  • Autophagy / physiology
  • Autophagy-Related Proteins / deficiency*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • NF-kappa B / metabolism
  • Signal Transduction
  • THP-1 Cells
  • Transfection
  • Vesicular Transport Proteins / deficiency*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism


  • ATG2B protein, human
  • Autophagy-Related Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • NF-kappa B
  • Vesicular Transport Proteins
  • CASP8 protein, human
  • Caspase 8