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Identification of a novel anti-apoptotic E3 ubiquitin ligase that ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, and ARTS

Authors
 Jung-bin Kim  ;  So Youn Kim  ;  Byeong Mo Kim  ;  Hunjin Lee  ;  Insook Kim  ;  Jeanho Yun  ;  Yejin Jo  ;  Taeheun Oh  ;  Yongsam Jo  ;  Hee-Don Chae  ;  Deug Y. Shin 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.288(17) : 12014-12021, 2013 
Journal Title
 JOURNAL OF BIOLOGICAL CHEMISTRY 
ISSN
 0021-9258 
Issue Date
2013
MeSH
Amino Acid Sequence ; Animals ; Apoptosis/physiology* ; Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Cell Line, Tumor ; High-Temperature Requirement A Serine Peptidase 2 ; Humans ; Inhibitor of Apoptosis Prooteins/genetics ; Inhibitor of Apoptosis Proteins/metabolism* ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism* ; Mice ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism* ; Molecular Sequence Data ; Proteolysis* ; Septins/genetics ; Septins/metabolism* ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism* ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism* ; Ubiquitination/physiology*
Abstract
Identification of new anti-apoptotic genes is important for understanding the molecular mechanisms underlying apoptosis and tumorigenesis. The present study identified a novel anti-apoptotic gene named AREL1, which encodes a HECT (homologous to E6-AP carboxyl terminus) family E3 ubiquitin ligase. AREL1 interacted with and ubiquitinated IAP antagonists such as SMAC, HtrA2, and ARTS. However, AREL1 was cytosolic and did not localize to nuclei or mitochondria. The interactions between AREL1 and the IAP antagonists were specific for apoptosis-stimulated cells, in which the IAP antagonists were released into the cytosol from mitochondria. Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists. Furthermore, the anti-apoptotic role of AREL1-mediated degradation of SMAC, HtrA2, and ARTS was shown by simultaneous knockdown of three IAP antagonists, which caused the inhibition of caspase-3 cleavage, XIAP degradation, and induction of apoptosis. Therefore, the present study suggests that AREL1-mediated ubiquitination and degradation of cytosolic forms of three IAP antagonists plays an important role in the regulation of apoptosis.
Files in This Item:
T201306076.pdf Download
DOI
10.1074/jbc.M112.436113
Appears in Collections:
5. Research Institutes (연구소) > Yonsei Integrative Research Institute for Cerebral & Cardiovascular Disease (뇌심혈관질환융합연구사업단) > 1. Journal Papers
Yonsei Authors
Kim, Byeong Mo(김병모) ORCID logo https://orcid.org/0000-0002-0582-3132
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/158411
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