SRCP1 Conveys Resistance to Polyglutamine Aggregation

• Published in: Molecular cell Vol. 71; no. 2; pp. 216 - 228.e7
• Main Authors: Santarriaga, Stephanie, Haver, Holly N., Kanack, Adam J., Fikejs, Alicia S., Sison, Samantha L., Egner, John M., Bostrom, Jonathan R., Seminary, Emily R., Hill, R. Blake, Link, Brian A., Ebert, Allison D., Scaglione, K. Matthew
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-07-2018
• Subjects: amyloid; Cell Line; chaperone; Dictyostelium - metabolism; Dictyostelium discoideum; HEK293 Cells; Humans; Huntington's disease; Molecular Chaperones - metabolism; Peptides - metabolism; polyglutamine; proteasome; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Serine - metabolism; ubiquitin; Ubiquitin - metabolism; Dictyostelium discoideum; proteasome; amyloid; chaperone; polyglutamine; Huntington's disease; ubiquitin
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.07.008

The polyglutamine (polyQ) diseases are a group of nine neurodegenerative diseases caused by the expansion of a polyQ tract that results in protein aggregation. Unlike other model organisms, Dictyostelium discoideum is a proteostatic outlier, naturally encoding long polyQ tracts yet resistant to polyQ aggregation. Here we identify serine-rich chaperone protein 1 (SRCP1) as a molecular chaperone that is necessary and sufficient to suppress polyQ aggregation. SRCP1 inhibits aggregation of polyQ-expanded proteins, allowing for their degradation via the proteasome, where SRCP1 is also degraded. SRCP1’s C-terminal domain is essential for its activity in cells, and peptides that mimic this domain suppress polyQ aggregation in vitro. Together our results identify a novel type of molecular chaperone and reveal how nature has dealt with the problem of polyQ aggregation.
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•SRCP1 is necessary for Dictyostelium’s resistance to polyglutamine aggregation•SRCP1 is sufficient to convey resistance to polyglutamine aggregation in other organisms•SRCP1 reduces the level of SDS-insoluble but not soluble polyQ-expanded protein•Residues in SRCP1’s C terminus are necessary for its function
Santarriaga et al. identify a molecular chaperone that is both necessary for Dictyostelium’s unusual resistance to polyglutamine aggregation and is sufficient to impart resistance to polyglutamine aggregation in other organisms. These findings describe how nature has dealt with the problem of polyglutamine aggregation.