Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion of the ataxin 7 (Atx7) protein. Previous studies reported that transcriptional dysregulation is vital for the pathogenesis of SCA7. However, how polyQ-expanded Atx7 leads to transcriptional dysregulation remains elusive.
Recently, a research team led by Dr. HU Hongyu from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, revealed that the aggregates of polyQ-expanded Atx7 specifically sequester its interacting partner ubiquitin-specific protease 22 (USP22) and impair its deubiquitinating function in the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex.
Atx7 and USP22 are both subunits of the deubiquitination module (DUBm) in the SAGA complex for transcriptional regulation. Dr. YANG Hui and her colleagues found that polyQ-expanded Atx7 can form aggregates or inclusions in nucleus and specifically sequester USP22 into insolubilities. To elucidate the mechanism underlying the sequestration and proteinopathy, they investigated the specific interaction between Atx7 and USP22, and defined that the zinc finger (ZnF) domain of Atx7 directly interacts with the N-terminus of USP22. Based on the hijacking model proposed previously (Yang et al.,Science Reports.2014, 4:6410), they examined whether sequestration of USP22 by polyQ-expanded Atx7 is dependent on the interaction. The ZnF domain mutants of Atx7, which lose the ability to interact with USP22, cannot sequester USP22 into aggregates or inclusions, demonstrating that specific interaction is vital for the sequestration by polyQ disease proteins. As USP22 is responsible for the deubiquitination of histone H2B, they studied the effect of polyQ-expanded Atx7 on the function of USP22 by detecting the level of monoubiquitinated H2B (H2Bub). Overexpression of polyQ-expanded Atx7 significantly increases the level of H2Bub, suggesting that the normal function of USP22 is impaired. Due to the importance of H2Bub for transcription regulation, this study provides insights into the molecular mechanism of the transcriptional dysfunction in SCA7 and potentially a therapeutic strategy for the disease.
This work entitled “Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex” was published online in the Journal of Biological Chemistry on September 4, 2015. This work was supported by the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Chinese Academy of Sciences.
AUTHOR CONTACT:
HU Hongyu, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China
Phone: 86-21-54921121;
E-mail: hyhu@sibcb.ac.cn
Fig. Aggregation of PolyQ-expanded Atx7 Specifically Sequesters USP22 and Deteriorates Its Deubiquitinating Function. The DUB module in the SAGA complex is comprised of four subunits: Atx7, USP22, Atx7L3, and ENY2. PolyQ-expanded Atx7 forms insoluble aggregates that sequester USP22 into a catalytically inactive state. The impaired DUB module loses the function to deubiquitinate mono-ubiquitinated histone H2B or H2A. (Image provided by Dr. HU Hongyu’s group).
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