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

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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Article numbere935
JournalCell Death and Disease
Volume4
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

Keywords

  • Apoptosis
  • Breast cancer
  • Caspase-8
  • HECTD3
  • Ubiquitination

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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