TY - JOUR
T1 - Transcription factors NRF2 and HSF1 have opposing functions in autophagy
AU - Dayalan Naidu, Sharadha
AU - Dikovskaya, Dina
AU - Gaurilcikaite, Egle
AU - Knatko, Elena V.
AU - Healy, Zachary R.
AU - Mohan, Hema
AU - Koh, Glenn
AU - Laurell, Axel
AU - Ball, Graeme
AU - Olagnier, David
AU - De La Vega, Laureano
AU - Ganley, Ian G.
AU - Talalay, Paul
AU - Dinkova-Kostova, Albena T.
N1 - Funding Information:
We are very grateful to Stephanie N. Jenkins (Johns Hopkins University, USA) for technical help with the mouse skin carcinogenesis experiment, Ronald Hicks (California State University East Bay, USA) for the synthesis of HBB2, Sonia Rocha (Univesrity of Dundee, UK) for generously providing U2OS cells, and Richard Morimoto (Northwestern University, USA) for generously providing HeLa-luc cells. The study was supported by Cancer Research UK (C20953/A18644), the BBSRC (BB/L01923X/1), and the Lewis B. and Dorothy Cullman Foundation. GB is supported by a MRC Next Generation Optical Microscopy Award (MR/K015869/1).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-017-11262-5
DO - 10.1038/s41598-017-11262-5
M3 - Article
C2 - 28887499
AN - SCOPUS:85028974944
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 11023
ER -