Transcription factors NRF2 and HSF1 have opposing functions in autophagy

Sharadha Dayalan Naidu, Dina Dikovskaya, Egle Gaurilcikaite, Elena Knatko, Zachary R. Healy, Hema Mohan, Glenn Koh, Axel Laurell, Graeme Ball, David Olagnier, Laureano de la Vega, Ian Ganley, Paul Talalay, Albena Dinkova-Kostova (Lead / Corresponding author)

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Abstract

Autophagy plays a critical role in the maintenance of cellular homeostasis by degrading proteins, lipids and organelles. Autophagy is activated in response to stress, but its regulation in the context of other stress response pathways, such as those mediated by heat shock factor 1 (HSF1)- and nuclear factor-erythroid 2 p45-related factor 2 (NRF2), is not well understood. We found that the Michael acceptor bis(2- hydoxybenzylidene)acetone (HBB2), a dual activator of NRF2 and HSF1, protects against the development of UV irradiation-mediated cutaneous squamous cell carcinoma in mice. We further show that HBB2 is an inducer of autophagy. In cells, HBB2 increases the levels of the autophagy-cargo protein p62/sequestosome 1, and the lipidated form of microtubule-associated protein light chain 3 isoform B. Activation of autophagy by HBB2 is impaired in NRF2-deficient cells, which have reduced autophagic flux and low basal and induced levels of p62. Conversely, HSF1- deficient cells have increased autophagic flux under both basal as well as HBB2- induced conditions, accompanied by increased p62 levels. Our findings suggest that NRF2 and HSF1 have opposing roles during autophagy, and illustrate the existence of tight mechanistic links between the cellular stress responses.
Original languageEnglish
Article number11023
Pages (from-to)1-12
Number of pages12
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 8 Sep 2017

Keywords

  • Journal Article

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    Dinkova-Kostova, Albena

    • Cellular Medicine - Professor (Teaching and Research) & Professor of Chemical Biology

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    Cite this

    Dayalan Naidu, S., Dikovskaya, D., Gaurilcikaite, E., Knatko, E., Healy, Z. R., Mohan, H., Koh, G., Laurell, A., Ball, G., Olagnier, D., de la Vega, L., Ganley, I., Talalay, P., & Dinkova-Kostova, A. (2017). Transcription factors NRF2 and HSF1 have opposing functions in autophagy. Scientific Reports, 7, 1-12. [11023]. https://doi.org/10.1038/s41598-017-11262-5