[HTML][HTML] The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8
Cell death & disease, 2013•nature.com
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 …
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 …
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.
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