The ubiquitin-conjugating enzyme UbcH6 regulates the transcriptional repression activity of the SCA1 gene product ataxin-1.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by ataxia and progressive motor deterioration. SCA1 is caused by expansion of the polyglutamine tract in the SCA1 gene product, ataxin-1. We previously reported that the E2 ubiquitin-conjugating enzyme UbcH6 interacts with and ubiquitinates the ataxin-1 proteins as an E2-substrate cognate pair in the ubiquitin-proteasome system. In the present study, we further investigated whether the function of ataxin-1 is associated with UbcH6 and found that UbcH6 regulates the transcriptional repression activity of ataxin-1. The overexpression of UbcH6 reduced the transcriptional repression activity of ataxin-1. Interestingly, ataxin-1(30Q) was more affected by the presence of UbcH6 than ataxin-1(82Q), implying that the length of the polyglutamine tract in ataxin-1 might be involved in determining the stability of ataxin-1. The half-life of ataxin-1(82Q) was longer than that of ataxin-1(30Q) in the presence of UbcH6. shRNAs targeting UbcH6 enhanced the transcriptional repression activity of ataxin-1. In addition, the overexpression of UbcH6 reduced the formation of ataxin-1 aggregates. Our studies demonstrate that UbcH6 modulates the transcriptional repression activity of ataxin-1 by modulating the degradation of ataxin-1, suggesting that UbcH6 may have some therapeutic potential in the treatment of SCA1.

• Authors: Soyeon Lee, Sunghoi Hong, Seongman Kang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 372 Issue 4 Pg. 735-40 (Aug 08 2008) ISSN: 1090-2104 [Electronic] United States
• PMID: 18519031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATXN1 protein, human
• Ataxin-1
• Ataxins
• Nerve Tissue Proteins
• Nuclear Proteins
• RNA, Small Interfering
• Repressor Proteins
• Luciferases
• UBE2E1 protein, human
• Ubiquitin-Conjugating Enzymes

Topics

• Ataxin-1
• Ataxins
• Cell Line
• Gene Expression Regulation
• Genes, Reporter
• Humans
• Luciferases (genetics)
• Nerve Tissue Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Repressor Proteins (genetics, metabolism)
• Spinocerebellar Ataxias (genetics, metabolism)
• Transcription, Genetic
• Ubiquitin-Conjugating Enzymes (genetics, metabolism)