HSP70 Inhibition Leads to the Activation of Proteasomal System under Mild Hyperthermia Conditions in Young and Senescent Fibroblasts

Oxid Med Cell Longev. 2020 Feb 27:2020:9369524. doi: 10.1155/2020/9369524. eCollection 2020.


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.

MeSH terms

  • Benzhydryl Compounds / pharmacology
  • Cellular Senescence* / genetics
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism*
  • Gene Silencing
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism
  • HSP70 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Response / genetics
  • Humans
  • Hyperthermia, Induced*
  • Male
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteostasis
  • Pyrrolidinones / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Benzhydryl Compounds
  • DNAJB1 protein, human
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • KNK 437
  • Pyrrolidinones
  • RNA, Messenger
  • Proteasome Endopeptidase Complex