title: Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP.
abstract: The mechanisms by which ubiquitin ligases are regulated remain poorly understood. Here we describe a series of molecular events that coordinately regulate CHIP, a neuroprotective E3 implicated in protein quality control. Through their opposing activities, the initiator E2, Ube2w, and the specialized deubiquitinating enzyme (DUB), ataxin-3, participate in initiating, regulating, and terminating the CHIP ubiquitination cycle. Monoubiquitination of CHIP by Ube2w stabilizes the interaction between CHIP and ataxin-3, which through its DUB activity limits the length of chains attached to CHIP substrates. Upon completion of substrate ubiquitination, ataxin-3 deubiquitinates CHIP, effectively terminating the reaction. Our results suggest that functional pairing of E3s with ataxin-3 or similar DUBs represents an important point of regulation in ubiquitin-dependent protein quality control. In addition, the results shed light on disease pathogenesis in SCA3, a neurodegenerative disorder caused by polyglutamine expansion in ataxin-3.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. kscaglio@umich.edu
authors.forename: K Matthew
authors.initials: KM
authors.lastname: Scaglione
authors.forename: Eszter
authors.initials: E
authors.lastname: Zavodszky
authors.forename: Sokol V
authors.initials: SV
authors.lastname: Todi
authors.forename: Srikanth
authors.initials: S
authors.lastname: Patury
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Edgardo
authors.initials: E
authors.lastname: Rodríguez-Lebrón
authors.forename: Svetlana
authors.initials: S
authors.lastname: Fischer
authors.forename: John
authors.initials: J
authors.lastname: Konen
authors.forename: Ana
authors.initials: A
authors.lastname: Djarmati
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C510626:UBE2W protein, human; D044763:Ubiquitin-Conjugating Enzymes; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; C092341:ATXN3 protein, human; D000067699:Ataxin-3