title: 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.affiliation: 1] Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China [2] State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Kong
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: Y-C
authors.initials: YC
authors.lastname: Hsieh
authors.forename: D
authors.initials: D
authors.lastname: Zhao
authors.forename: X
authors.initials: X
authors.lastname: Zhi
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology
chemical_list: D053181:Caspase 8; D044767:Ubiquitin-Protein Ligases; C526919:HECTD3 protein, human