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.

• Authors: Y Li, Y Kong, Z Zhou, H Chen, Z Wang, Y-C Hsieh, D Zhao, X Zhi, J Huang, J Zhang, H Li, C Chen
• Journal: Cell death & disease (Cell Death Dis) Vol. 4 Pg. e935 (Nov 28 2013) ISSN: 2041-4889 [Electronic] England
• PMID: 24287696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hectd3 protein, human
• Ubiquitin-Protein Ligases
• Caspase 8

Topics

• Apoptosis (genetics, physiology)
• Caspase 8 (genetics, metabolism)
• Cell Line
• Cell Survival (genetics, physiology)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Protein Binding
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination (genetics, physiology)