期刊
FRONTIERS IN GENETICS
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2018.00379
关键词
Slx5; STUbL; SUMO; ubiquitin; Htt
资金
- NSF [1051970]
- Commonwealth of Virginia's Alzheimer's and Related Diseases Research Award Fund (ARDRAF) [17-1]
- Broderick Family/Goldman Sachs TDAP award
- Intramural Research Program of the National Cancer Institute, National Institutes of Health
- Bailey-Huston Research fund
- HHMI Science Education and Research program
- Charles Center Honors Fellowship
- Summer research fellowships
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1051970] Funding Source: National Science Foundation
Cell viability and gene expression profiles are altered in cellular models of neurodegenerative disorders such as Huntington's Disease (HD). Using the yeast model system, we show that the SUMO-targeted ubiquitin ligase (STUbL) Slx5 reduces the toxicity and abnormal transcriptional activity associated with a mutant, aggregation-prone fragment of huntingtin (Htt), the causative agent of HD. We demonstrate that expression of an aggregation-prone Htt construct with 103 glutamine residues (1030), but not the non-expanded form (250), results in severe growth defects in slx5 Delta and slx8 Delta cells. Since Slx5 is a nuclear protein and because Htt expression affects gene transcription, we assessed the effect of STUbLs on the transcriptional properties of aggregation-prone Htt. Expression of Htt 25Q and 55Q fused to the Gal4 activation domain (AD) resulted in reporter gene auto-activation. Remarkably, the auto-activation of Htt constructs was abolished by expression of Slx5 fused to the Ga14 DNA-binding domain (BD-Slx5). In support of these observations, RNF4, the human ortholog of Slx5, curbs the aberrant transcriptional activity of aggregation-prone Htt in yeast and a variety of cultured human cell lines. Functionally, we find that an extra copy of SLX5 specifically reduces Htt aggregates in the cytosol as well as chromatin-associated Htt aggregates in the nucleus. Finally, using RNA sequencing, we identified and confirmed specific targets of Htt's transcriptional activity that are modulated by Slx5. In summary, this study of STUbLs uncovers a conserved pathway that counteracts the accumulation of aggregating, transcriptionally active Htt (and possibly other poly-glutamine expanded proteins) on chromatin in both yeast and in mammalian cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据