HSPA1A Protects Cells from Thermal Stress by Impeding ESCRT-0-Mediated Autophagic Flux in Epidermal Thermoresistance

Thermoresistance is a physiological phenomenon relevant to noninvasive laser treatments for skin esthetics and tumor removal, although the underlying mechanism remains elusive. We hypothesized that HSPA1A may regulate autophagy by reducing ESCRT-0 and/or STAM2 levels, which could lead to thermal protection from cell death. In this study, we showed that thermoresistance was induced in mouse epidermal tissue and HaCaT cells by heating at 45 degrees C for 10 minutes. Moreover, HSPA1A levels were increased in thermoresistant mouse epidermis and HaCaT cells. HSPA1A was highly involved in protecting cells from thermal cytotoxicity, as evidenced by the knockdown or overexpression assays of the HSPA1A gene. In addition, ESCRT-0 and STAM2 levels were dramatically decreased in thermoresistant cells, which was mediated by HSPA1A binding to STAM2, particularly through HSPA1A amino acids 395-509. Furthermore, the loss of ESCRT-0 and/or STAM2 in response to HSPA1A-STAM2 binding regulated autophagy by impeding autophagosome-lysosome fusion and abolishing autophagic flux in cellular thermoresistance, significantly reducing thermal cytotoxicity and promoting cell survival. To our knowledge, it is previously unreported that HSPA1A-ESCRT-0 and/or STAM2 modulates heat-induced resistance by inhibiting autophagic flux. In summary, the results of this study demonstrate that the mechanisms of thermoresistance may have clinical relevance for noninvasive or minimally invasive thermal therapeutics.