Department of Microbiology and Physiological Systems
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Cells | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Enzymes and Coenzymes | Genetic Phenomena | Genetics and Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases
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 (103Q), but not the non-expanded form (25Q), results in severe growth defects in slx5Delta and slx8Delta 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 Gal4 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.
Htt, STUbL, SUMO, Slx5, ubiquitin
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Copyright © 2018 Ohkuni, Pasupala, Peek, Holloway, Sclar, Levy-Myers, Baker, Basrai and Kerscher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Front Genet. 2018 Sep 18;9:379. doi: 10.3389/fgene.2018.00379. eCollection 2018. Link to article on publisher's site
Frontiers in genetics
Ohkuni K, Pasupala N, Peek J, Holloway GL, Sclar GD, Levy-Myers R, Baker RE, Basrai MA, Kerscher O. (2018). SUMO-Targeted Ubiquitin Ligases (STUbLs) Reduce the Toxicity and Abnormal Transcriptional Activity Associated With a Mutant, Aggregation-Prone Fragment of Huntingtin. Open Access Articles. https://doi.org/10.3389/fgene.2018.00379. Retrieved from https://escholarship.umassmed.edu/oapubs/3622
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Amino Acids, Peptides, and Proteins Commons, Biochemistry, Biophysics, and Structural Biology Commons, Cells Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Molecular and Cellular Neuroscience Commons, Nervous System Diseases Commons