SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans

Abstract

The mammalian Nrf/CNC proteins (Nrf1, Nrf2, Nrf3, p45 NF-E2) perform a wide range of cellular protective and maintenance functions. The most thoroughly described of these proteins, Nrf2, is best known as a regulator of antioxidant and xenobiotic defense, but more recently has been implicated in additional functions that include proteostasis and metabolic regulation. In the nematode Caenorhabditis elegans, which offers many advantages for genetic analyses, the Nrf/CNC proteins are represented by their ortholog SKN-1. Although SKN-1 has diverged in aspects of how it binds DNA, it exhibits remarkable functional conservation with Nrf/CNC proteins in other species and regulates many of the same target gene families. C. elegans may therefore have considerable predictive value as a discovery model for understanding how mammalian Nrf/CNC proteins function and are regulated in vivo. Work in C. elegans indicates that SKN-1 regulation is surprisingly complex and is influenced by numerous growth, nutrient, and metabolic signals. SKN-1 is also involved in a wide range of homeostatic functions that extend well beyond the canonical Nrf2 function in responses to acute stress. Importantly, SKN-1 plays a central role in diverse genetic and pharmacologic interventions that promote C. elegans longevity, suggesting that mechanisms regulated by SKN-1 may be of conserved importance in aging. These C. elegans studies predict that mammalian Nrf/CNC protein functions and regulation may be similarly complex and that the proteins and processes that they regulate are likely to have a major influence on mammalian life- and healthspan.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…PMK‐1‐dependent phosphorylation of SKN‐1 is vital for stress‐induced increases in its activity (Blackwell et al., 2015; Inoue et al., 2005). Hence, we hypothesized that these kinases might be required for tBOOH‐induced increases in NHR‐49 levels and/or fmo‐2 expression.…”

“…Moreover, we find that nhr‐49 is also required for the induction of tBOOH‐induced genes by acute fasting. Collectively, our data suggest that, in addition to its role in regulating lipid metabolism, NHR‐49 participates in a cytoprotective acute stress response program that functions parallel to and independently of SKN‐1/Nrf2 and HLH‐30/TFEB signaling (Blackwell et al., 2015; Lapierre et al., 2013). This raises the possibility that NHR‐49's pro‐longevity function, for example in glp‐1 mutants (Ratnappan et al., 2014), may involve modulating both lipid metabolism and stress defenses (Figure 6).…”

“…In the nematode Caenorhabditis elegans , the Nrf2 ortholog SKiNhead (SKN‐1) implements a wide range of homeostatic and stress responses in response to internal and external stimuli (Blackwell, Steinbaugh, Hourihan, Ewald & Isik, 2015). Although the transcription factors DAF‐16, HSF‐1, HLH‐30, and HIF‐1 activate a variety of stress/pathogen‐protective responses, SKN‐1 is especially important to maintain redox balance and defend against oxidative stress caused by xenobiotics that target GSH and cause protein unfolding (Blackwell et al., 2015; Miranda‐Vizuete & Veal, 2016). Nevertheless, distinct responses are initiated in response to different oxidants (Blackwell et al., 2015; Wu, Deonarine, Przybysz, Strange & Choe, 2016).…”

“…Although the transcription factors DAF‐16, HSF‐1, HLH‐30, and HIF‐1 activate a variety of stress/pathogen‐protective responses, SKN‐1 is especially important to maintain redox balance and defend against oxidative stress caused by xenobiotics that target GSH and cause protein unfolding (Blackwell et al., 2015; Miranda‐Vizuete & Veal, 2016). Nevertheless, distinct responses are initiated in response to different oxidants (Blackwell et al., 2015; Wu, Deonarine, Przybysz, Strange & Choe, 2016). For example, the organic peroxide tert‐butyl‐hydroperoxide (tBOOH) elicits a transcriptional response that is largely skn‐1 ‐independent (Oliveira et al., 2009).…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…56 Furthermore, Nrf2 signaling has been documented to confer resistance to oxidative stress and promote healthy aging in Caenorhabditis elegans. 57,58 Reduced activation of Nrf2 in aging has been reported to be associated with various chronic diseases, such as progressive respiratory disease, neurodegeneration, and inflammatory disorders. 59 Age-dependent decline in the levels and/or activation of Nrf2 is accompanied by reduced expression of cytoprotective genes and increased susceptibility to oxidative injury.…”