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The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8.

ABSTRACT: Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival.

SUBMITTER: Li Y

PROVIDER: S-EPMC3847339 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8.

Li Y Y Kong Y Y Zhou Z Z Chen H H Wang Z Z Hsieh Y-C YC Zhao D D Zhi X X Huang J J Zhang J J Li H H Chen C C

Cell death & disease 20131128

Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent ...[more]

PMID: 24287696

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