Protein aggregation mediates stoichiometry of protein complexes in aneuploid cells

• Published in: Genes & development Vol. 33; no. 15-16; pp. 1031 - 1047
• Main Authors: Brennan, Christopher M, Vaites, Laura Pontano, Wells, Jonathan N, Santaguida, Stefano, Paulo, Joao A, Storchova, Zuzana, Harper, J Wade, Marsh, Joseph A, Amon, Angelika
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-08-2019
• Subjects: Aneuploidy; Cytosol - metabolism; Dosage Compensation, Genetic - physiology; Humans; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; Protein Aggregates - genetics; Protein Aggregation, Pathological; Protein Subunits - metabolism; Proteolysis; Research Paper; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; aneuploidy; protein aggregation; protein homeostasis
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.327494.119

Aneuploidy, a condition characterized by chromosome gains and losses, causes reduced fitness and numerous cellular stresses, including increased protein aggregation. Here, we identify protein complex stoichiometry imbalances as a major cause of protein aggregation in aneuploid cells. Subunits of protein complexes encoded on excess chromosomes aggregate in aneuploid cells, which is suppressed when expression of other subunits is coordinately altered. We further show that excess subunits are either degraded or aggregate and that protein aggregation is nearly as effective as protein degradation at lowering levels of excess proteins. Our study explains why proteotoxic stress is a universal feature of the aneuploid state and reveals protein aggregation as a form of dosage compensation to cope with disproportionate expression of protein complex subunits.