Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells

Jack Llewellyn, Venkatesh Mallikarjun, Ellen Appleton, Maria Osipova, Hamish T. J. Gilbert, Stephen M. Richardson, Simon J. Hubbard, Joe Swift

Research output: Contribution to journalArticlepeer-review

Abstract

Cells respond to stress by synthesising chaperone proteins that seek to correct protein misfolding and maintain function. However, abrogation of protein homeostasis is a hallmark of ageing, leading to loss of function and the formation of proteotoxic aggregates characteristic of pathology. Consequently, discovering the underlying molecular causes of this deterioration in proteostasis is key to designing effective interventions to disease, or to maintaining cell health in regenerative medicine strategies. Here, we examined primary human mesenchymal stem cells (hMSCs), cultured to a point of replicative senescence and subjected to heat shock, as an in vitro model of the ageing stress response. Multi -omics analysis showed how components of homeostasis were reduced in senescent cells, caused by dysregulation of a functional network of chaperones, thereby limiting proteostatic competence. Time-resolved analysis of the primary response factors, including those regulating heat shock protein 70 kDa (HSPA1A), revealed that regulatory control is essentially translational. Senescent cells have a reduced capacity for chaperone protein translation and misfolded protein turnover, driven by downregulation of ribosomal proteins and loss of the E3 ubiquitin ligase CHIP which marks misfolded proteins for degradation. This limits the cell’s stress response and subsequent recovery. A kinetic model recapitulated these reduced capacities and predicted an accumulation of misfolded protein, a hypothesis supported by evidence of systematic changes to protein fold state. These results thus establish a specific loss of regulatory capacity at the protein, rather than transcript, level and uncover underlying systematic links between ageing and loss of protein homeostasis.
Original languageEnglish
Article numbere2210745120
JournalProceedings of the National Academy of Sciences
Volume120
Issue number14
Early online date29 Mar 2023
DOIs
Publication statusPublished - 4 Apr 2023

Keywords

  • Proteostasis network
  • mesenchymal stem cells
  • molecular chaperones
  • proteomics
  • senescence

Fingerprint

Dive into the research topics of 'Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells'. Together they form a unique fingerprint.

Cite this