An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress

• 成果类型: Article
• 署名作者: Alasady, Milad J.; Koeva, Martina; Takagishi, Seesha R.; Segal, Dmitri; Amici, David R.; Smith, Roger S.; Ansel, Daniel J.; Lindquist, Susan; Whitesell, Luke; Bartom, Elizabeth T.; Taipale, Mikko; Mendillo, Marc L.
• 署名单位: Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Ann & Robert H. Lurie Children's Hospital of Chicago; Robert H. Lurie Comprehensive Cancer Center; Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12575
• DOI: 10.1073/pnas.2313370121
• 发表日期: 2024-07-16
• 关键词: heat-shock proteins; hsf1; jmjd6; methylation

摘要

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- 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.