Senescence inhibits the chaperone response to thermal stress

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.

Loss of cytoskeletal proteostasis links dysregulation of cell size and mechanotransduction in mesenchymal stem cell senescence

“…Downregulation of CCT/TRiC is not specific to MSCs grown on hydrogels. Specifically, we have also observed similar CCT/TRiC downregulation in MSCs grown on tissue culture plastic (Llewellyn et al, 2021). Furthermore, gene expression for CCT/TRiC subunits have also been observed to be downregulated with age in human brain tissue (Brehme et al, 2014).…”

Mimicking physiological stiffness or oxygen levels in vitro reorganizes mesenchymal stem cells machinery toward a more naïve phenotype

“…More specifically, subunits of the chaperonincontaining T-complex (TRiC) were found to be upregulated alongside other chaperones, such as HSP90 (Figure 2D, Supplementary Table 2). Chaperones play a crucial role in maintaining proteostasis and are associated with cellular aging, since senescent MSCs have been described to exhibit dysregulation in the chaperone network, leading to the accumulation of misfolded proteins (48,49). Also, late passage MSCs (P5-P18) are known to express reduced levels of both TRiC and HSP90 (49).…”

“…Chaperones play a crucial role in maintaining proteostasis and are associated with cellular aging, since senescent MSCs have been described to exhibit dysregulation in the chaperone network, leading to the accumulation of misfolded proteins (48,49). Also, late passage MSCs (P5-P18) are known to express reduced levels of both TRiC and HSP90 (49). In addition, these chaperones are also described to be implicated in telomere maintenance, a finding supported by our GO enrichment data (Figure 2C) (50,51).…”

Contribution of Extracellular Vesicles and Molecular Chaperones in Age-Related Neurodegenerative Disorders of the CNS

“…Considering that heat shock disrupts protein structure and promotes the accumulation of misfolded proteins, it can be implied that CCT8 and CCT2 help organisms to live longer through stabilizing protein homeostasis during aging [ 89 ]. Due to a drastic imbalance between excessive amounts of protein aggregates and available molecular chaperones during aging, both expression levels and the proper protein folding capability of CS may be altered by the toxicity of accumulated misfolded proteins as a common molecular pathway in numerous human diseases [ 90 , 91 , 92 , 93 , 94 ]. The aforementioned process may be accelerated by various cellular stressors that can prematurely stimulate the same senescence phenotype as seen in senescence induced by telomere shortening [ 95 ].…”