期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-11262-5
关键词
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资金
- Cancer Research UK [C20953/A18644]
- BBSRC [BB/L01923X/1]
- Lewis B. and Dorothy Cullman Foundation
- MRC [MR/K015869/1]
- BBSRC [BB/L01923X/1] Funding Source: UKRI
- MRC [MC_UU_12016/4, MR/K015869/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L01923X/1] Funding Source: researchfish
- Cancer Research UK [18644, 22869] Funding Source: researchfish
- Medical Research Council [MC_UU_12016/4, MR/K015869/1] Funding Source: researchfish
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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