Ube2w and Ataxin-3 Coordinately Regulate the Ubiquitin Ligase CHIP

K. Matthew Scaglione*, Eszter Zavodszky, Sokol V. Todi, Srikanth Patury, Ping Xu, Edgardo Rodríguez-Lebrón, Svetlana Fischer, John Konen, Ana Djarmati, Junmin Peng, Jason E. Gestwicki, Henry L. Paulson

*Corresponding author for this work
81 Citations (Scopus)


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.

Original languageEnglish
JournalMolecular Cell
Issue number4
Pages (from-to)599-612
Number of pages14
Publication statusPublished - 19.08.2011


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