Spatial sequestration and detoxification of Huntingtin by the ribosome quality control complex

被引:52
作者
Yang, Junsheng [1 ]
Hao, Xinxin [1 ]
Cao, Xiuling [1 ]
Liu, Beidong [1 ]
Nystrom, Thomas [2 ]
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.
引用
收藏
页数:14
相关论文
共 57 条
[1]   The src homology domain 3 (SH3) of a yeast type I myosin, Myo5p, binds to verprolin and is required for targeting to sites of actin polarization [J].
Anderson, BL ;
Boldogh, I ;
Evangelista, M ;
Boone, C ;
Greene, LA ;
Pon, LA .
JOURNAL OF CELL BIOLOGY, 1998, 141 (06) :1357-1370
[2]   Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].
Arrasate, M ;
Mitra, S ;
Schweitzer, ES ;
Segal, MR ;
Finkbeiner, S .
NATURE, 2004, 431 (7010) :805-810
[3]   HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span [J].
Baird, Nathan A. ;
Douglas, Peter M. ;
Simic, Milos S. ;
Grant, Ana R. ;
Moresco, James J. ;
Wolff, Suzanne C. ;
Yates, John R., III ;
Manning, Gerard ;
Dillin, Andrew .
SCIENCE, 2014, 346 (6207) :360-363
[4]   Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers [J].
Behrends, Christian ;
Langer, Carola A. ;
Boteva, Raina ;
Bottcher, Ulrike M. ;
Stemp, Markus J. ;
Schaffar, Gregor ;
Rao, Bharathi Vasudeva ;
Giese, Armin ;
Kretzschmar, Hans ;
Siegers, Katja ;
Hartl, F. Ulrich .
MOLECULAR CELL, 2006, 23 (06) :887-897
[5]   Role of a ribosome-associated E3 ubiquitin ligase in protein quality control [J].
Bengtson, Mario H. ;
Joazeiro, Claudio A. P. .
NATURE, 2010, 467 (7314) :470-473
[6]   Heat Shock Response Activation Exacerbates Inclusion Body Formation in a Cellular Model of Huntington Disease [J].
Bersuker, Kirill ;
Hipp, Mark S. ;
Calamini, Barbara ;
Morimoto, Richard I. ;
Kopito, Ron R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (33) :23633-23638
[7]   GO::TermFinder - open source software for accessing Gene Ontology information and finding significantly enriched Gene Ontology terms associated with a list of genes [J].
Boyle, EI ;
Weng, SA ;
Gollub, J ;
Jin, H ;
Botstein, D ;
Cherry, JM ;
Sherlock, G .
BIOINFORMATICS, 2004, 20 (18) :3710-3715
[8]   A Ribosome-Bound Quality Control Complex Triggers Degradation of Nascent Peptides and Signals Translation Stress [J].
Brandman, Onn ;
Stewart-Ornstein, Jacob ;
Wong, Daisy ;
Larson, Adam ;
Williams, Christopher C. ;
Li, Gene-Wei ;
Zhou, Sharleen ;
King, David ;
Shen, Peter S. ;
Weibezahn, Jimena ;
Dunn, Joshua G. ;
Rouskin, Silvi ;
Inada, Toshifumi ;
Frost, Adam ;
Weissman, Jonathan S. .
CELL, 2012, 151 (05) :1042-1054
[9]   The BioGRID interaction database:: 2008 update [J].
Breitkreutz, Bobby-Joe ;
Stark, Chris ;
Reguly, Teresa ;
Boucher, Lorrie ;
Breitkreutz, Ashton ;
Livstone, Michael ;
Oughtred, Rose ;
Lackner, Daniel H. ;
Bahler, Jurg ;
Wood, Valerie ;
Dolinski, Kara ;
Tyers, Mike .
NUCLEIC ACIDS RESEARCH, 2008, 36 :D637-D640
[10]   A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration [J].
Chu, Jessie ;
Hong, Nancy A. ;
Masuda, Claudio A. ;
Jenkins, Brian V. ;
Nelms, Keats A. ;
Goodnow, Christopher C. ;
Glynne, Richard J. ;
Wu, Hua ;
Masliah, Eliezer ;
Joazeiro, Claudio A. P. ;
Kay, Steve A. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (07) :2097-2103