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  • Title: An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress.
    Author: Alasady MJ, Koeva M, Takagishi SR, Segal D, Amici DR, Smith RS, Ansel DJ, Lindquist S, Whitesell L, Bartom ET, Taipale M, Mendillo ML.
    Journal: Proc Natl Acad Sci U S A; 2024 Jul 16; 121(29):e2313370121. PubMed ID: 38985769.
    Abstract:
    Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified Jumonji domain-containing protein 6 (JMJD6) as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a noncanonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces heat shock protein 70 (HSP70) R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role in cellular adaptation to proteotoxic stress.
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