Regulation of misfolded protein aggregation and degradation by SUMOylation in budding yeast.

Abstract

Protein misfolding is linked to many neurodegenerative disorders, such as Huntington's disease. The increase of glutamine-encoding CAG repeats in the first exon of huntingtin (HTT) causes Huntington's disease. Protein fragments of Htt exon 1 with polyQ expansion (mutant HTT, mHtt) are prone to aggregation, resulting in oligomers, amyloid fibrils, or large inclusion bodies. Previous studies demonstrate mHtt SUMOylation, a process of covalent attachment of small ubiquitin-like modifiers (SUMO) to target proteins. Protein polySUMOylation further triggers its ubiquitination and segregation by the polySUMO axis. Here, we examined how SUMOylation regulates aggregation and degradation of Htt103QP-GFP, a model mHtt, in budding yeast. We first confirmed Htt103QP-GFP SUMOylation in budding yeast. We also found that recruitment of the SUMO E2-conjugating enzyme to Htt103QP-GFP accelerates its aggregation, but recruitment of a SUMO protease to Htt103QP-GFP delays this process. Disruption of the polySUMO axis led to increased Htt103QP-GFP aggregation. Interestingly, the results from fluorescence recovery after photobleaching assay and treatment with a biomolecular condensate-disrupting chemical indicate that SUMOylation accelerates biomolecular condensate formation of Htt103QP-GFP. Importantly, impaired SUMOylation delays Htt103QP-GFP proteasomal degradation and accelerates formation of SDS-insoluble Htt103QP-GFP aggregates. Together, these results indicate that SUMOylation facilitates proteasomal degradation of misfolded proteins by retaining their solubility.