title: Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1α.
abstract: Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system. We also observed that the serine-threonine kinase IRE1 involved in endoplasmic reticulum (ER) stress responses is activated in mutant Htt-expressing cells in culture as well as in the striatum of mutant Htt transgenic (BACHD) mice. Usp14 interacted with IRE1 in control cells but less in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1α in mutant Htt-overexpressing cells and to protect against cell degeneration and caspase-3 activation. These results show that ER stress-mediated IRE1 activation is part of mutant Htt toxicity and that this is counteracted by Usp14 expression. Usp14 effectively reduced cellular aggregates and counteracted cell degeneration indicating an important role of this protein in mutant Htt-induced cell toxicity.
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Alise
authors.initials: A
authors.lastname: Hyrskyluoto
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Céline
authors.initials: C
authors.lastname: Bruelle
authors.affiliation: Translational Neuroendocrine Research Unit, Lund University, Lund SE-221 84, Sweden and.
authors.forename: Sofia H
authors.initials: SH
authors.lastname: Lundh
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Hai Thi
authors.initials: HT
authors.lastname: Do
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kivinen
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rappou
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Reijonen
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Tuure
authors.initials: T
authors.lastname: Waltimo
authors.affiliation: Translational Neuroendocrine Research Unit, Lund University, Lund SE-221 84, Sweden and.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Petersén
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland, dan.lindholm@helsinki.fi.
authors.forename: Dan
authors.initials: D
authors.lastname: Lindholm
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki FIN-00290, Finland, Minerva Foundation Institute for Medical Research, Helsinki, Finland, Division of Child Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Korhonen
mesh_terms: D000818:Animals; D002449:Cell Aggregation; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D025801:Ubiquitin; C469268:Usp14 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex