Soluble klotho induces the heat shock factor 1 through EGR1 expression

Abstract Klotho is an antiaging protein that has multiple functions. The purpose of this study is to investigate whether soluble klotho plays a role in cellular stress response pathways. We found that klotho deficiency (kl −/− ) largely decreased HSF1 levels and impaired heat shock protein expression. Interestingly, recombinant soluble klotho‐induced HSF1 and HSPs such as HSP90, HSP70, and HSP27 in kl −/− mouse embryonic fibroblasts (MEFs). Soluble Klotho treatment also induced cell proliferation and HSF1 promoter activity in MEF kl −/− cells in a concentration‐dependent manner. Furthermore, using point mutagenesis, we identified regulatory/binding sites of transcription factors EGR1 regulated by soluble klotho in the HSF1 promoter. Taken together, our findings unravel the molecular basis of klotho and provide molecular evidence supporting a direct interaction between soluble klotho and HSF1‐mediated stress response pathway.