Hormetic Heat Shock Enhances Autophagy through HSF1 in Retinal Pigment Epithelium Cells

Funding Information: Funding: This research work was supported by Business Finland (1786/31/2018), Karolinska Institutet Funds and Foundations and the Swedish Eye Foundation (Ögonfonden), Academy of Finland grant number of (296840, 333302), Kuopio University Hospital VTR grant number of (5503743), the Sigrid Juselius Foundation, the Päivikki and Sakari Sohlberg Foundation, and the University of Eastern Finland strategical support the Finnish Eye Foundation. Publisher Copyright: © 2022 by the authorsLicensee MDPI, Basel, Switzerland.To maintain homeostasis, cells have evolved stress-response pathways to cope with exogenous and endogenous stress factors. Diverse stresses at high doses may be detrimental, albeit low doses of stress, known as hormesis, can be beneficial. Upon exposure to stress, such as temperature rise, the conventional heat shock response (HSR) regulated by the heat shock transcription factor 1 (HSF1) facilitates refolding of misfolded proteins with the help of heat shock proteins (HSPs). However, the role and molecular mechanisms underlying the beneficial effects of HSR with other clearance processes, such as autophagy, remain poorly understood. In this study, human ARPE-19 cells, an in vitro model of retinal pigment epithelium, were treated with hormetic heat shock (HHS) and the autophagy expression profile was examined using quantitative PCR (qPCR), immunoblotting, immunoprecipitation, and immunofluorescence. We demonstrate that HHS enhances the expression of fundamental autophagy-associated genes in ARPE-19 cells through the activation of HSF1. HHS transiently increases the level of SQSTM1 and LC3B-II and activates autophagy. These findings reveal a role for autophagic HSF1-regulated functions and demonstrate the contribution of autophagy to hormesis in the HSR by improving proteostasis.Peer reviewe