Transcription factors NRF2 and HSF1 have opposing functions in autophagy

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.

HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

“…In principle, HSPB8 and BAG3 could affect p62 levels via multiple mechanisms, including transcription and autophagic degradation. For instance, evidence suggests that BAG3 can modulate transcription factors [i.e., HSF1 (77) and Nrf2 (the present study)], which are reported to regulate p62 levels (33,34,78,79). Our preliminary results suggest that p62 mRNA levels are reduced in HSPB8-and BAG3-depleted cells.…”

The role of Nrf2 signaling in counteracting neurodegenerative diseases

“…Nrf2 promotes autophagy via induction of the autophagosome cargo protein p62/sequestosome‐1 (p62/SQSTM1) and other autophagy‐related genes . Knockdown of Nrf2 reduces autophagic flux, whereas pharmacological Nrf2 activation promotes autophagy, and this closely correlates with changes in the levels of p62/SQSTM1 .…”

“…Nrf2 promotes autophagy via induction of the autophagosome cargo protein p62/sequestosome‐1 (p62/SQSTM1) and other autophagy‐related genes . Knockdown of Nrf2 reduces autophagic flux, whereas pharmacological Nrf2 activation promotes autophagy, and this closely correlates with changes in the levels of p62/SQSTM1 . This area of research is of particular importance given the strong association between neurological phenotypes and the presence of accumulated misfolded proteins in affected brains, and deficiency of the protein degradation machinery in neurodegenerative diseases.…”

Genome-Wide CRISPR Screen Reveals Autophagy Disruption as the Convergence Mechanism That Regulates the NRF2 Transcription Factor

“…As mentioned, arsenic can inhibit autophagic flux, allowing for p62-dependent sequestration of KEAP1 and eventual NRF2 activation; additionally, silencing of autophagy genes ATG5, ATG7, and BECN1 is known to activate NRF2. Intriguingly, the NRF2 activator bis(2hydoxybenzylidene)acetone induces autophagy more poorly in NRF2-deficient cells, suggesting that NRF2 plays a critical role in autophagy (78). This screen suggests that links between NRF2 and autophagy are more intimate and complicated than what has been discovered previously.…”