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bioRxiv · 10.1101/2021.06.15.448532

Senescence inhibits the chaperone response to thermal stress

Llewellyn, J.·Mallikarjun, V.·Appleton, E.·Osipova, M.·Gilbert, H. T.·Richardson, S. M.·Hubbard, S. J.·Swift, J.
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Abstract

Cells respond to stress by synthesising chaperone proteins that correct protein misfolding to maintain function. However, protein homeostasis is lost in ageing, leading to aggregates characteristic of protein-folding diseases. Whilst much is known about how these diseases progress, discovering what causes protein-folding to deteriorate could be key to their prevention. 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. We found through proteomic analysis that the maintenance of homeostasis deteriorated in senescent cells. Time-resolved analysis of factors regulating heat shock protein 70 kDa (HSPA1A) revealed a lack of capacities for protein turnover and translation to be key factors in limiting the stress response during senescence. A kinetic model predicted a consequence of these reduced capacities to be the accumulation of misfolded protein, a hypothesis supported by evidence of systematic changes to protein fold state. These results thus further our understanding of the underlying mechanistic links between ageing and loss of protein homeostasis.

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Llewellyn, J., Mallikarjun, V., Appleton, E., Osipova, M., Gilbert, H. T., Richardson, S. M., Hubbard, S. J., Swift, J.. 2021-06-15. Senescence inhibits the chaperone response to thermal stress. https://doi.org/10.1101/2021.06.15.448532

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