title: Ubiquitin ligase ITCH recruitment suppresses the aggregation and cellular toxicity of cytoplasmic misfolded proteins.
abstract: The protein quality control (QC) system protects cells against cellular toxicity induced by misfolded proteins and maintains overall cellular fitness. Inefficient clearance of or failure to degrade damaged proteins causes several diseases, especially age-linked neurodegenerative disorders. Attenuation of misfolded protein degradation under severe stress conditions leads to the rapid over-accumulation of toxic proteinaceous aggregates in the cytoplasmic compartment. However, the precise cytoplasmic quality control degradation mechanism is unknown. In the present study, we demonstrate that the Nedd4-like E3 ubiquitin ligase ITCH specifically interacts with mutant bona fide misfolded proteins and colocalizes with their perinuclear aggregates. In a cell culture model, we demonstrate ITCH recruitment by cytoplasmic inclusions containing polyglutamine-expanded huntingtin or ataxin-3 proteins. Transient overexpression of ITCH dramatically induced the degradation of thermally denatured misfolded luciferase protein. Partial depletion of ITCH increased the rate of aggregate formation and cell death generated by expanded polyglutamine proteins. Finally, we demonstrate that overexpression of ITCH alleviates the cytotoxic potential of expanded polyglutamine proteins and reduces aggregation. These observations indicate that ITCH is involved in the cytosolic quality control pathway and may help to explain how abnormal proteins are targeted by QC ubiquitin-protein ligases.
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India 342011.
authors.forename: Deepak
authors.initials: D
authors.lastname: Chhangani
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India 342011.
authors.forename: Arun
authors.initials: A
authors.lastname: Upadhyay
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India 342011.
authors.forename: Ayeman
authors.initials: A
authors.lastname: Amanullah
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India 342011.
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Joshi
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India 342011.
authors.forename: Amit
authors.initials: A
authors.lastname: Mishra
mesh_terms: D000067699:Ataxin-3; D002460:Cell Line; D006801:Humans; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates / Q000235:genetics*; D017510:Protein Folding; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D066329:Protein Aggregates; D012097:Repressor Proteins; D025801:Ubiquitin; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; C092341:ATXN3 protein, human; D000067699:Ataxin-3