Regulation of protein homeostasis in aneuploid cancer cells

• Applicant: Dr. Prince Saforo Amponsah
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology ; Biochemistry
• Term: from 2022 to 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510268075

• Final Report Year: 2024

Final Report Abstract

Aberrant chromosomal content, or aneuploidy, profoundly affects cellular physiology. Chromosome gain, called polysomy, disrupts cellular proteostasis due to overexpression of numerous proteins. Constitutively polysomic human cells manifest proteome imbalance, exhibit defective protein folding and accumulate protein aggregates that are positive for the autophagy receptor sequestosome 1 (SQSTM1 or p62). I found that the abundance of p62 protein and p62-positive aggregates scale with the degree of proteotoxic stress (i.e., number of surplus protein coding genes) and correlate with increased protein aggregation. Systematic profiling of p62 interactors separately by immunoprecipitation and APEX2-dependent proximity biotinylation in the cytosol, followed by mass spectrometry, revealed that mitochondrial proteins are the predominant cytosolic interactors of p62 in polysomic cells. Concomitantly, compared to parental disomes, polysomic cells harbor perinuclearly clustered mitochondria that exhibit significant defects, including reduced precursor protein import. Taken together, the data indicate that proteotoxic stress induced by chromosome gain compromises mitochondrial functions and leads to the sequestration of mitochondrial precursor proteins into cytosolic p62-positive protein aggregates. Interestingly, proximity profiling of the p62-associated candidates in the autophagosomal lumen in polysomic cells revealed that the mitochondrial proteins enriched with p62 in the cytosol are not removed by p62 via autophagy. This work sheds new insight into the consequences of aneuploidy and provide novel, physiologically relevant model system to study the link between cytosolic protein imbalance, chronic proteotoxic stress and mitochondrial homeostasis.

Publications

• Sublinear scaling of the cellular proteome with ploidy. Nature Communications, 13(1).
  Yahya, G.; Menges, P.; Amponsah, P. S.; Ngandiri, D. A.; Schulz, D.; Wallek, A.; Kulak, N.; Mann, M.; Cramer, P.; Savage, V.; Räschle, M. & Storchova, Z.
  
• Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62. openRxiv.
  Amponsah, Prince Saforo; Bökenkamp, Jan-Eric; Lenhard, Svenja; Behrends, Christian; Herrmann, Johannes Martin; Räschle, Markus & Storchová, Zuzana
  
• How do genome abnormalities impact mitochondrial homeostasis?. BIOspektrum, 31(1), 23-25.
  Kurpa, Olha & Amponsah, Prince Saforo
  
• The proteostasis burden of aneuploidy. Biological Chemistry, 406(5-7), 331-343.
  Amponsah, Prince Saforo & Storchová, Zuzana