• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • Heat shock facilitates the folding of various proteins


    Heat shock facilitates the folding of various proteins as mediated by the HSP family and can stabilize mutant proteins. HS has been reported to facilitate maturation of WT-HERG as well as mutant HERG by activating the HSF family [15]. HSF-1, 2, and 4 were reported to be expressed in humans. HSF-1 is a master regulator of Hsp70 and Hsp90. HSF-2 plays roles in the development nk1 receptor of the nk1 receptor and reproductive organs and acts as a major regulator of the proteostasis capacity against febrile-range thermal stress to prevent the accumulation of misfolded proteins [16]. HSF-4, which possesses transcriptional repressor properties in vivo, inhibits basal transcription of Hsp27 and Hsp90 in cultured cells [17]. In the present study, we found that HSF-1, but not HSF- 2 or 4, increased the expression of mature A78T-HERG protein. These results suggest that HSF-1 stabilizes A78T-HERG protein, promotes its transport to the plasma membrane, and increases the membrane current IKr. The ubiquitin proteasome system in cardiomyocytes, including HL-1 cells and neonatal rat cardiomyocytes, involves three activities: chymotrypsin-like, trypsin-like, and caspase-like activities. The degradation of several ion channel proteins showed similar time courses between cardiomyocytes and HEK293 cells, indicating no difference in ubiquitin–proteasome system activities in these cells. Thus, mutant HERG proteins such as A78T-HERG may be degraded through the ubiquitin–proteasome system in cardiomyocytes as well [18]. Accordingly, the clinical implications of our results are as follows. To date, many studies have shown that maturation of mutant HERG proteins can be improved by low temperature or HS and by application of E-4031 or a gastroprokinetic agent such as cisapride [19–21]. GGA is a non-toxic acyclic isoprenoid compound with a retinoid skeleton that increases Hsp70 expression by activating HSF-1 [22]. In the present study, GGA at the clinical concentration of 200nM facilitated maturation of the A78T-HERG protein, suggesting that GGA is of therapeutic value for patients with LQT2 caused by the A78T mutation in HERG.
    Conflict of interest
    Financial support This study was supported by a Grant in-Aid for scientific research from the Ministry of Education, Culture, Science, Sports and Technology of Japan (25670110 to I. H.).