TY - JOUR
T1 - Targeting the ESCRT-III component CHMP2A for noncanonical Caspase-8 activation on autophagosomal membranes
AU - Hattori, Tatsuya
AU - Takahashi, Yoshinori
AU - Chen, Longgui
AU - Tang, Zhenyuan
AU - Wills, Carson A.
AU - Liang, Xinwen
AU - Wang, Hong Gang
N1 - Funding Information:
Acknowledgements This work was supported by the NIH grants GM127954 and CA222349, the Lois High Berstler Research Endowment Fund, and the Four Diamonds Fund. Confocal images were generated using the Leica SP8 microscope (NIH Shared Instrumentation grant S10OD010756-01A1) located in the Penn State College of Medicine Microscopy Imaging Core Facility.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2021/2
Y1 - 2021/2
N2 - Autophagosomal membranes can serve as activation platforms for intracellular death-inducing signaling complexes (iDISCs) to initiate Caspase-8-dependent apoptosis. In this study, we explore the impact of ESCRT-III-dependent phagophore closure on iDISC assemblies and cell death in osteosarcoma and neuroblastoma cells. Inhibition of phagophore closure by conditional depletion of CHMP2A, an ESCRT-III component, stabilizes iDISCs on immature autophagosomal membranes and induces Caspase-8-dependent cell death. Importantly, suppression of the iDISC formation via deletion of ATG7, an E1 enzyme for ubiquitin-like autophagy-related proteins, blocks Caspase-8 activation and cell death following CHMP2A depletion. Although DR5 expression and TRAIL-induced apoptosis are enhanced in CHMP2A-depleted cells, the canonical extrinsic pathway of apoptosis is not responsible for the initiation of cell death by CHMP2A depletion. Furthermore, the loss of CHMP2A impairs neuroblastoma tumor growth associated with decreased autophagy and increased apoptosis in vivo. Together, these findings indicate that inhibition of the ESCRT-III-dependent autophagosome sealing process triggers noncanonical Caspase-8 activation and apoptosis, which may open new avenues for therapeutic targeting of autophagy in cancer.
AB - Autophagosomal membranes can serve as activation platforms for intracellular death-inducing signaling complexes (iDISCs) to initiate Caspase-8-dependent apoptosis. In this study, we explore the impact of ESCRT-III-dependent phagophore closure on iDISC assemblies and cell death in osteosarcoma and neuroblastoma cells. Inhibition of phagophore closure by conditional depletion of CHMP2A, an ESCRT-III component, stabilizes iDISCs on immature autophagosomal membranes and induces Caspase-8-dependent cell death. Importantly, suppression of the iDISC formation via deletion of ATG7, an E1 enzyme for ubiquitin-like autophagy-related proteins, blocks Caspase-8 activation and cell death following CHMP2A depletion. Although DR5 expression and TRAIL-induced apoptosis are enhanced in CHMP2A-depleted cells, the canonical extrinsic pathway of apoptosis is not responsible for the initiation of cell death by CHMP2A depletion. Furthermore, the loss of CHMP2A impairs neuroblastoma tumor growth associated with decreased autophagy and increased apoptosis in vivo. Together, these findings indicate that inhibition of the ESCRT-III-dependent autophagosome sealing process triggers noncanonical Caspase-8 activation and apoptosis, which may open new avenues for therapeutic targeting of autophagy in cancer.
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U2 - 10.1038/s41418-020-00610-0
DO - 10.1038/s41418-020-00610-0
M3 - Article
C2 - 32807832
AN - SCOPUS:85089468980
SN - 1350-9047
VL - 28
SP - 657
EP - 670
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 2
ER -