Abstract
Aging has been characterized with the accumulation of oxidized proteins, as a consequence of progressive decline in proteostasis capacity. Among others, proteasomal system is an efficient protein turnover complex to avoid aggregation of oxidized proteins. Heat shock protein 70 (HSP70) is another critical player that is involved in some key processes including the correct folding of misfolded proteins and targeting aggregated proteins to the proteasome for rapid degradation. The aim of this study was to determine the role of proteasomal system and heat shock proteins to maintain proteome balance during replicative senescence in mild hyperthermia conditions. Our results demonstrated that HSP40/70 machinery is induced by mild hyperthermia conditions independent from senescence conditions. Since HSP70 is largely responsible for the rapidly inducible cell protection following hyperthermia, the activation of “heat shock response” resulted in the elevation of HSP40/70 expressions as well as the proteasome activity. Interestingly, when HSP70 expression was inhibited, increased proteasomal activation was shown to be responsive to mild hyperthermia. Since HSP70 is involved in various stress-related pathways such as oxidative and endoplasmic reticulum stress, depletion of HSP70 expression may induce proteasomal degradation to maintain proteome balance of the cell. Thus, our data suggests that in mild heat stress conditions, molecular chaperone HSP70 plays an important role to avoid protein oxidation and aggregation; however, activities of proteasomal system are induced when HSP70 expression is depleted.
Highlights
Aging is characterized by the loss of cellular function that results in the accumulation of oxidative damage to macromolecules such as lipids, DNA, and proteins [1]
Our results revealed that in mild hyperthermia, Heat shock protein 70 (HSP70) increased to cope with the heat stress; when HSP70 is inhibited, the proteasomal degradation is activated to maintain the proteome balance
Recent studies indicated that elevated protein damage during aging is likely to be aggravated by the decrease in heat shock response and heat shock proteins (HSPs) levels and, as a result, by the deterioration of protein quality control [17]
Summary
Aging is characterized by the loss of cellular function that results in the accumulation of oxidative damage to macromolecules such as lipids, DNA, and proteins [1]. Proteostasis state of the organisms is maintained by the balanced activity of protein synthesis, folding, and degradation network [2, 3]. In senescent organisms, oxidized proteins are accumulated due to the reduced efficiency of heat shock proteins (HSPs) and decline in the activity of degradation mechanisms such as proteasomal system [4, 5]. HSPs, which act as molecular chaperones, are known to have key roles in the maintenance of the proteostasis that work coordinately for the correct folding of misfolded proteins [6]. Among the members of the heat shock proteins, recent studies have pointed to 70 kDa heat shock protein
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