Aggregation of Polyglutamine-Expanded Ataxin-7 Specifically Sequesters Ubiquitin-Specific Protease 22 and Deteriorates Its Deubiquitinating Function in SAGA Complex [Protein Structure and Folding]

July 20th, 2015 by Yang, H., Liu, S., He, W.-T., Zhao, J., Jiang, L.-L., Hu, H.-Y.

Human ataxin-7 (Atx7) is a component of the deubiquitination module (DUBm) in SAGA complex for transcriptional regulation; while expansion of its polyglutamine (polyQ) tract leads to spinocerebellar ataxia type 7 (SCA7). However, how polyQ expansion of Atx7 affects the DUBm function remains elusive. We investigated the effects of polyQ-expanded Atx7 on ubiquitin-specific protease (USP22), an interacting partner of Atx7 functioning in deubiquitination of histone H2B. The results showed that the inclusions or aggregates formed by polyQ-expanded Atx7 specifically sequester USP22 through their interactions mediated by the N-terminal zinc-finger (ZnF) domain of Atx7. Mutation of the ZnF domain in Atx7 that disrupts its interaction with USP22 dramatically abolishes sequestration of USP22. Moreover, polyQ expansion of Atx7 decreases the deubiquitinating activity of USP22 and consequently increases the level of mono-ubiquitinated H2B. Thus, we propose that polyQ-expanded Atx7 forms insoluble aggregates that sequester USP22 into catalytically inactive state, then the impaired DUBm loses the function to deubiquitinate mono-ubiquitinated histone H2B or H2A. This may result in dysfunction of the SAGA complex and transcriptional dysregulation in SCA7 disease.
  • Posted in Journal of Biological Chemistry, Publications
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