title: Spatial sequestration and detoxification of Huntingtin by the ribosome quality control complex.
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 ltn1∆ 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.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Hao
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
authors.forename: Beidong
authors.identifier: http://orcid.org/0000-0001-6052-8411
authors.initials: B
authors.lastname: Liu
authors.affiliation: Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0001-5489-2903
authors.initials: T
authors.lastname: Nyström
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D000071058:Huntingtin Protein / Q000378:metabolism*; D002479:Inclusion Bodies / Q000378:metabolism*; D059748:Proteolysis; D012270:Ribosomes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; C067168:HSF1 protein, S cerevisiae; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C552998:Ltn1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases
keywords: Huntington's disease; S. cerevisiae; cell biology; genome-wide screen; hsf1; protein aggregation; ribosome quality control complex