Protein aggregation mediates stoichiometry of protein complexes in aneuploid cells

  1. Angelika Amon1,2,3
  1. 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  2. 2Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  3. 3Paul F. Glenn Center for Biology of Aging Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  4. 4Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
  5. 5MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;
  6. 6Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy;
  7. 7Technische Universität Kaiserslautern, 67663 Kaiserslautern, Germany
  1. Corresponding author: angelika{at}mit.edu
  1. 8 These authors contributed equally to this work.

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.

Keywords

Footnotes

  • Received April 10, 2019.
  • Accepted May 13, 2019.

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