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

Författare och institution:
Junsheng Yang (Institutionen för kemi och molekylärbiologi); Xinxin Hao (Institutionen för kemi och molekylärbiologi); Xiuling Cao (Institutionen för kemi och molekylärbiologi); Beidong Liu (Institutionen för kemi och molekylärbiologi); Thomas Nyström (Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi)
Publicerad i:
Elife, 5 s. article no. e11792
ISSN:
2050-084X
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2016
Språk:
engelska
Fulltextlänk:
Sammanfattning (abstract):
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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
Cell- och molekylärbiologi ->
Cellbiologi
Nyckelord:
inclusion-body formation, e3 ubiquitin ligase, heat-shock response, saccharomyces-cerevisiae, polyglutamine aggregation, chaperone proteins, mutant huntingtin, gene-function, yeast model, life-span, Life Sciences & Biomedicine
Postens nummer:
235784
Posten skapad:
2016-05-02 15:42
Posten ändrad:
2016-05-02 15:43

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