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

Milad J. Alasady; Martina Koeva; Seesha R. Takagishi; Dmitri Segal; David R. Amici; Roger S. Smith; Daniel J. Ansel; Susan Lindquist; Luke Whitesell; Elizabeth T. Bartom; Mikko Taipale; Marc L. Mendillo

doi:10.1073/pnas.2313370121

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

Milad J. Alasady, Martina Koeva, Seesha R. Takagishi, Dmitri Segal, David R. Amici, Roger S. Smith, Daniel J. Ansel, Susan Lindquist, Luke Whitesell, Elizabeth T. Bartom, Mikko Taipale, Marc L. Mendillo^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Article number	e2313370121
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	121
Issue number	29
DOIs	https://doi.org/10.1073/pnas.2313370121
State	Published - Jul 16 2024

Funding

ACKNOWLEDGMENTS. We thank Stacy Marshall and Emily Rendleman for their help with next-generation DNA sequencing. We thank Dr. Daniel Foltz for his assistance with Zeiss LSM800 microscopy. We thank Dr. Vladimir Gelfand for providing the LI-COR Odyssey Imager. M.L.M. was supported by the NIH (1R01GM144617-01), the Susan G. Komen Foundation (CCR17488145), and Lynn Sage Scholar awards. M.J.A. was supported by the Northwestern University Training Program in Signal Transduction and Cancer (T32 CA070085). E.T.B. was supported by the National Cancer Institute of the NIH (R50CA221848). D.R.A. and R.S.S. were supported by the NIH (T32GM008152) and D.R.A. was also supported by the NIH (F30CA264513).

Keywords

HSF1
JMJD6
proteostasis

ASJC Scopus subject areas

General

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10.1073/pnas.2313370121

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Alasady, M. J., Koeva, M., Takagishi, S. R., Segal, D., Amici, D. R., Smith, R. S., Ansel, D. J., Lindquist, S., Whitesell, L., Bartom, E. T., Taipale, M., & Mendillo, M. L. (2024). An HSF1–JMJD6–HSP feedback circuit promotes cell adaptation to proteotoxic stress. Proceedings of the National Academy of Sciences of the United States of America, 121(29), Article e2313370121. https://doi.org/10.1073/pnas.2313370121

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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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Alasady, MJ, Koeva, M, Takagishi, SR, Segal, D, Amici, DR, Smith, RS, Ansel, DJ, Lindquist, S, Whitesell, L, Bartom, ET, Taipale, M & Mendillo, ML 2024, 'An HSF1–JMJD6–HSP feedback circuit promotes cell adaptation to proteotoxic stress', Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 29, e2313370121. https://doi.org/10.1073/pnas.2313370121

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AU - Amici, David R.

AU - Smith, Roger S.

AU - Ansel, Daniel J.

AU - Lindquist, Susan

AU - Whitesell, Luke

AU - Bartom, Elizabeth T.

AU - Taipale, Mikko

AU - Mendillo, Marc L.

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

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