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学科主题基础医学
The E3 Ligase Smurf1 Regulates Wolfram Syndrome Protein Stability at the Endoplasmic Reticulum
Guo, Xing1,5,6; Shen, Shan2,3; Song, Shanshan1,5,6; He, Shan1; Cui, Yu1; Xing, Guichun1; Wang, Jian1; Yin, Yuxin4; Fan, Libin2,3; He, Fuchu1,5,6; Zhang, Lingqiang1,2,3
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
2011-05-20
DOI10.1074/jbc.M111.225615
286期:20页:18037-18047
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
资助者National Basic Research Programs ; National Natural Science Foundation ; National Key Technologies R& ; D Program for New Drugs ; National Basic Research Programs ; National Natural Science Foundation ; National Key Technologies R& ; D Program for New Drugs
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]PANCREATIC BETA-CELLS ; UBIQUITIN LIGASES ; DIDMOAD SYNDROME ; WFS1 GENE ; DEGRADATION ; STRESS ; EXPRESSION ; P53 ; ACTIVATION ; POLARITY
英文摘要

The HECT-type ubiquitin ligase (E3) Smad ubiquitination regulatory factor 1 (Smurf1) targets various substrates, including Smad1/5, RhoA, Prickle 1, MEKK2, and JunB for degradation and thereby regulates adult bone formation and embryonic development. Here, we identify the endoplasmic reticulum (ER)-localized Wolfram syndrome protein (WFS1) as a specific degradation substrate of Smurf1. Mutations in the WFS1 gene cause Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy. WFS1 negatively regulates the ER stress response, and WFS1 deficiency in mice increases ER stress and triggers apoptosis. We show that Smurf1 interacts with WFS1 at the ER and promotes the ubiquitination and proteasomal degradation of WFS1. A C-terminal luminal region in WFS1, including residues 667-700, is involved in this degradation. Wild-type WFS1 as well as a subset of WFS1 mutants that include this degron region are susceptible to Smurf1-mediated degradation. By contrast, pathophysiological deletion mutants of WFS1 lacking the degron, such as W648X, Y660X, and Q667X, are resistant to degradation by Smurf1. Depletion of Smurf1 by RNA interference results in increased WFS1 and decreased ATF6 alpha levels. Furthermore, we show that ER stress induces Smurf1 degradation and WFS1 up-regulation. These findings reveal for the first time that Smurf1 targets an ER-localized protein for degradation and that Smurf1 is regulated by ER stress.

语种英语
所属项目编号2011CB910602 ; 2007CB914601 ; 2010CB912202 ; 30830029 ; 2009ZX09503-002 ; 2009ZX09301-002
资助者National Basic Research Programs ; National Natural Science Foundation ; National Key Technologies R& ; D Program for New Drugs ; National Basic Research Programs ; National Natural Science Foundation ; National Key Technologies R& ; D Program for New Drugs
WOS记录号WOS:000290585200065
引用统计
被引频次:28[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/52408
专题基础医学院_病理学系
作者单位1.Beijing Inst Radiat Med, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 100850, Peoples R China
2.Anhui Med Univ, Dept Biol, Hefei 230032, Anhui, Peoples R China
3.Anhui Med Univ, Cell Biol Lab, Hefei 230032, Anhui, Peoples R China
4.Peking Univ, Sch Basic Med Sci, Dept Pathol, Beijing 100191, Peoples R China
5.Chinese Acad Med Sci, Inst Basic Med Sci, Dept Med Genet, Beijing 100730, Peoples R China
6.Peking Union Med Coll, Beijing 100730, Peoples R China
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Guo, Xing,Shen, Shan,Song, Shanshan,et al. The E3 Ligase Smurf1 Regulates Wolfram Syndrome Protein Stability at the Endoplasmic Reticulum[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2011,286(20):18037-18047.
APA Guo, Xing.,Shen, Shan.,Song, Shanshan.,He, Shan.,Cui, Yu.,...&Zhang, Lingqiang.(2011).The E3 Ligase Smurf1 Regulates Wolfram Syndrome Protein Stability at the Endoplasmic Reticulum.JOURNAL OF BIOLOGICAL CHEMISTRY,286(20),18037-18047.
MLA Guo, Xing,et al."The E3 Ligase Smurf1 Regulates Wolfram Syndrome Protein Stability at the Endoplasmic Reticulum".JOURNAL OF BIOLOGICAL CHEMISTRY 286.20(2011):18037-18047.
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