@article{2cfd9f768bce4af19452a67de13c9bfa,
title = "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.",
author = "Zhenyuan Tang and Yoshinori Takahashi and Chong Chen and Ying Liu and Haiyan He and Nikolaos Tsotakos and Serfass, {Jacob M.} and Gebru, {Melat T.} and Han Chen and Young, {Megan M.} and Wang, {Hong Gang}",
note = "Funding Information: Acknowledgements. This work was supported by the Hyundai Hope on Wheels Foundation, Lois High Berstler, and Four Diamonds Fund. Authors would like to thank Dr. Kenichiro Doi, Neelam Desai, and Longgui Chen for technical support. We thank Nate Sheaffer, Joseph Bednarzyk, and Jade Vogel from the Penn State College of Autophagy assays. Autophagy assays were performed as previously described.55 Briefly, cells were starved in the presence or absence of 100 nM Bafilomycin A1 prior to immunoblotting. The intensity of LC3-II and β-actin were quantified using LI-COR Biosciences Image Studio 5.0 software, and LC3-II intensities were normalized to β-actin. Basal autophagic flux (1) and starvation-induced autophagic flux (2) were calculated using the following formulas:56 (1) [(complete media with BafA1 − complete media)/(complete media with BafA1)] × 100; (2) [(starvation media with BafA1 − starvation media)/(starvation media with BafA1)] × 100. All data were normalized to WT. Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/cdd.2017.133",
language = "English (US)",
volume = "24",
pages = "2127--2138",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "12",
}