共 57 条
Spatial sequestration and detoxification of Huntingtin by the ribosome quality control complex
被引:52
作者:

Yang, Junsheng
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机构:
Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden

Hao, Xinxin
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Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden

Cao, Xiuling
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Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden

Liu, Beidong
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机构:
Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden

论文数: 引用数:
h-index:
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机构:
[1] Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden
[2] Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden
来源:
ELIFE
|
2016年
/
5卷
基金:
瑞典研究理事会;
欧洲研究理事会;
关键词:
INCLUSION-BODY FORMATION;
E3 UBIQUITIN LIGASE;
SACCHAROMYCES-CEREVISIAE;
MUTANT HUNTINGTIN;
PROTEINS;
GENE;
AGGREGATION;
TOXICITY;
DISEASE;
CYTOTOXICITY;
D O I:
10.7554/eLife.11792
中图分类号:
Q [生物科学];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
Huntington disease (HD) is a neurological disorder caused by polyglutamine expansions in mutated Huntingtin (mHtt) proteins, rendering them prone to form inclusion bodies (IB). We report that in yeast, such IB formation is a factor-dependent process subjected to age related decline. A genome-wide, high-content imaging approach, identified the E3 ubiquitin ligase, Ltn1 of the ribosome quality control complex (RQC) as a key factor required for IB formation, ubiquitination, and detoxification of model mHtt. The failure of Itn1 Delta cells to manage mHtt was traced to another RQC component, Tae2, and inappropriate control of heat shock transcription factor, Hsf1, activity. Moreover, super-resolution microscopy revealed that mHtt toxicity in RQC-deficient cells was accompanied by multiple mHtt aggregates altering actin cytoskeletal structures and retarding endocytosis. The data demonstrates that spatial sequestration of mHtt into IBs is policed by the RQC-Hsf1 regulatory system and that such compartmentalization, rather than ubiquitination, is key to mHtt detoxification.
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Phenomix Corp, San Diego, CA 92121 USA Scripps Res Inst, Dept Biochem, Inst Childhood & Neglected Dis, La Jolla, CA 90237 USA

Masliah, Eliezer
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Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA Scripps Res Inst, Dept Biochem, Inst Childhood & Neglected Dis, La Jolla, CA 90237 USA

Joazeiro, Claudio A. P.
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Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA Scripps Res Inst, Dept Biochem, Inst Childhood & Neglected Dis, La Jolla, CA 90237 USA

Kay, Steve A.
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Scripps Res Inst, Dept Biochem, Inst Childhood & Neglected Dis, La Jolla, CA 90237 USA Scripps Res Inst, Dept Biochem, Inst Childhood & Neglected Dis, La Jolla, CA 90237 USA