Dynamic recruitment of active proteasomes into polyglutamine initiated inclusion bodies

• Published in: FEBS letters Vol. 588; no. 1; pp. 151 - 159
• Main Authors: Schipper-Krom, Sabine, Juenemann, Katrin, Jansen, Anne H., Wiemhoefer, Anne, van den Nieuwendijk, Rianne, Smith, Donna L., Hink, Mark A., Bates, Gillian P., Overkleeft, Hermen, Ovaa, Huib, Reits, Eric
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 03.01.2014
• Subjects: ABP; activity-based probe; Aggregate; animal models; Animals; Blotting, Western; Brain - metabolism; Brain - pathology; Cell Line, Tumor; Disease Models, Animal; Female; fluorescence; fluorescence recovery after photobleaching; FRAP; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HEK293 Cells; HeLa Cells; Humans; Huntingtin Protein; Huntington; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - pathology; huntington's disease; inclusion bodies; Inclusion Bodies - genetics; Inclusion Bodies - metabolism; inclusion body; Male; mHtt; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Microscopy, Confocal; mutant huntingtin; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; neurodegenerative diseases; neurons; Peptides - genetics; Peptides - metabolism; Polyglutamine; polyQ; Proteasome; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Protein Binding; protein bodies; protein folding; tetracysteine; Trinucleotide Repeat Expansion - genetics; Ubiquitin; ubiquitin–proteasome system; UPS; Ubiquitin; Polyglutamine; mHtt; Huntington; Ub; ABP; C4; IB; UPS; FRAP; polyQ; HD; Aggregate; Proteasome; huntington’s disease; ubiquitin–proteasome system; tetracysteine; inclusion body; activity-based probe; mutant huntingtin; fluorescence recovery after photobleaching
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1016/j.febslet.2013.11.023

•Proteasomes are reversibly recruited to polyglutamine aggregates.•Proteasomes directly interact with the polyglutamine fragments.•Recruited proteasomes remain accessible to substrates.•The UPS does not become impaired by polyglutamine aggregates. Neurodegenerative disorders such as Huntington’s disease are hallmarked by neuronal intracellular inclusion body formation. Whether proteasomes are irreversibly recruited into inclusion bodies in these protein misfolding disorders is a controversial subject. In addition, it has been proposed that the proteasomes may become clogged by the aggregated protein fragments, leading to impairment of the ubiquitin–proteasome system. Here, we show by fluorescence pulse-chase experiments in living cells that proteasomes are dynamically and reversibly recruited into inclusion bodies. As these recruited proteasomes remain catalytically active and accessible to substrates, our results challenge the concept of proteasome sequestration and impairment in Huntington’s disease, and support the reported absence of proteasome impairment in mouse models of Huntington’s disease.