Protein Aggregation Mediates Stoichiometry of Protein Complexes in Aneuploid Cells

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2019 Jun 15

PMID 31196865

Citations 63

Authors

Christopher M Brennan

Laura Pontano Vaites

Jonathan N Wells

Stefano Santaguida

Joao A Paulo

Zuzana Storchova

J Wade Harper

Joseph A Marsh

Angelika Amon

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer.

Rendo V, Schubert M, Khuu N, Suarez Peredo Rodriguez M, Whyte D, Ling X Nat Commun. 2025; 16(1):1077.

PMID: 39870664 PMC: 11772776. DOI: 10.1038/s41467-025-56301-2.

TanGIBLE: A selective probe for evaluating hydrophobicity-exposed defective proteins in live cells.

Iwasa Y, Miyata S, Tomita T, Yokota N, Miyauchi M, Mori R J Cell Biol. 2025; 224(3.

PMID: 39812643 PMC: 11734626. DOI: 10.1083/jcb.202109010.

Preserve or destroy: Orphan protein proteostasis and the heat shock response.

Ali A, Paracha S, Pincus D J Cell Biol. 2024; 223(12).

PMID: 39545954 PMC: 11572482. DOI: 10.1083/jcb.202407123.

The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast.

Dutcher H, Hose J, Howe H, Rojas J, Gasch A PLoS Genet. 2024; 20(10):e1011454.

PMID: 39453980 PMC: 11540229. DOI: 10.1371/journal.pgen.1011454.

Global profiling of protein complex dynamics with an experimental library of protein interaction markers.

Dorig C, Marulli C, Peskett T, Volkmar N, Pantolini L, Studer G Nat Biotechnol. 2024; .

PMID: 39415059 DOI: 10.1038/s41587-024-02432-8.

References

Santaguida S, Amon A . Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat Rev Mol Cell Biol. 2015; 16(8):473-85. DOI: 10.1038/nrm4025. View

Torres E, Dephoure N, Panneerselvam A, Tucker C, Whittaker C, Gygi S . Identification of aneuploidy-tolerating mutations. Cell. 2010; 143(1):71-83. PMC: 2993244. DOI: 10.1016/j.cell.2010.08.038. View

Koplin A, Preissler S, Ilina Y, Koch M, Scior A, Erhardt M . A dual function for chaperones SSB-RAC and the NAC nascent polypeptide-associated complex on ribosomes. J Cell Biol. 2010; 189(1):57-68. PMC: 2854369. DOI: 10.1083/jcb.200910074. View

Caughey B, Lansbury P . Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003; 26:267-98. DOI: 10.1146/annurev.neuro.26.010302.081142. View

Levy E, De S, Teichmann S . Cellular crowding imposes global constraints on the chemistry and evolution of proteomes. Proc Natl Acad Sci U S A. 2012; 109(50):20461-6. PMC: 3528536. DOI: 10.1073/pnas.1209312109. View

Santaguida S, Vasile E, White E, Amon A . Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev. 2015; 29(19):2010-21. PMC: 4604343. DOI: 10.1101/gad.269118.115. View

Shevchenko A, Tomas H, Havlis J, Olsen J, Mann M . In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc. 2007; 1(6):2856-60. DOI: 10.1038/nprot.2006.468. View

Gibson D, Young L, Chuang R, Venter J, Hutchison 3rd C, Smith H . Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods. 2009; 6(5):343-5. DOI: 10.1038/nmeth.1318. View

Goncalves E, Fragoulis A, Garcia-Alonso L, Cramer T, Saez-Rodriguez J, Beltrao P . Widespread Post-transcriptional Attenuation of Genomic Copy-Number Variation in Cancer. Cell Syst. 2017; 5(4):386-398.e4. PMC: 5660600. DOI: 10.1016/j.cels.2017.08.013. View

10.

Vizcaino J, Csordas A, Del-Toro N, Dianes J, Griss J, Lavidas I . 2016 update of the PRIDE database and its related tools. Nucleic Acids Res. 2015; 44(D1):D447-56. PMC: 4702828. DOI: 10.1093/nar/gkv1145. View

11.

Taggart J, Li G . Production of Protein-Complex Components Is Stoichiometric and Lacks General Feedback Regulation in Eukaryotes. Cell Syst. 2018; 7(6):580-589.e4. PMC: 6659121. DOI: 10.1016/j.cels.2018.11.003. View

12.

Oromendia A, Dodgson S, Amon A . Aneuploidy causes proteotoxic stress in yeast. Genes Dev. 2012; 26(24):2696-708. PMC: 3533075. DOI: 10.1101/gad.207407.112. View

13.

Elias J, Gygi S . Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat Methods. 2007; 4(3):207-14. DOI: 10.1038/nmeth1019. View

14.

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

15.

Tang Y, Williams B, Siegel J, Amon A . Identification of aneuploidy-selective antiproliferation compounds. Cell. 2011; 144(4):499-512. PMC: 3532042. DOI: 10.1016/j.cell.2011.01.017. View

16.

Marsh J, Hernandez H, Hall Z, Ahnert S, Perica T, Robinson C . Protein complexes are under evolutionary selection to assemble via ordered pathways. Cell. 2013; 153(2):461-70. PMC: 4009401. DOI: 10.1016/j.cell.2013.02.044. View

17.

Elias J, Gygi S . Target-decoy search strategy for mass spectrometry-based proteomics. Methods Mol Biol. 2009; 604:55-71. PMC: 2922680. DOI: 10.1007/978-1-60761-444-9_5. View

18.

David D, Ollikainen N, Trinidad J, Cary M, Burlingame A, Kenyon C . Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol. 2010; 8(8):e1000450. PMC: 2919420. DOI: 10.1371/journal.pbio.1000450. View

19.

Pu S, Wong J, Turner B, Cho E, Wodak S . Up-to-date catalogues of yeast protein complexes. Nucleic Acids Res. 2008; 37(3):825-31. PMC: 2647312. DOI: 10.1093/nar/gkn1005. View

20.

Longtine M, McKenzie 3rd A, DeMarini D, Shah N, Wach A, Brachat A . Additional modules for versatile and economical PCR-based gene deletion and modification in Saccharomyces cerevisiae. Yeast. 1998; 14(10):953-61. DOI: 10.1002/(SICI)1097-0061(199807)14:10<953::AID-YEA293>3.0.CO;2-U. View