Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegans

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center
Cell (Impact Factor: 32.24). 04/2008; 132(6):1025-38. DOI: 10.1016/j.cell.2008.01.030
Source: PubMed


Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.

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Available from: T Keith Blackwell, Dec 10, 2014
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    • "Our previous studies demonstrated that SKN-1 is under direct regulation by a WD40 repeat protein named WDR-23; WDR-23 directly binds to SKN-1 to restrain its nuclear accumulation under basal conditions presumably by recruiting the transcription factor to a ubiquitin ligase (Choe et al. 2009). SKN-1 also functions downstream of target of rapamycin (TOR) and insulin/IGF-1-like signaling (IIS) (Tullet et al. 2008; Wang et al. 2010; Robida-Stubbs et al. 2012) pathways that influence longevity and is required for lifespan extension by dietary restriction (Tang and Choe 2015; Bishop and Guarente 2007). Regulation of SKN-1 and the mechanisms by which it influences longevity and stress resistance are highly active areas of research (Blackwell et al. 2015; Ewald et al. 2015; Steinbaugh et al. 2015; Tang and Choe 2015; Dresen et al. 2015; Chew et al. 2015). "
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    ABSTRACT: In Caenorhabditis elegans, the transcription factor SKN-1 has emerged as a central coordinator of stress responses and longevity increasing the need for genetic tools to study its regulation and function. However, current loss of function alleles cause fully penetrant maternal effect embryonic lethality and must be maintained with genetic balancers that require careful monitoring and labor intensive strategies to obtain large populations. In this study, we identified a strong, but viable skn-1 hypomorphic allele skn-1(zj0015) from a genetic screen for suppressors of wdr-23, a direct regulator of the transcription factor. skn-1(zj0015) is a point mutation in an intron that causes mis-splicing of a fraction of mRNA and strongly reduces wildtype mRNA levels of the two long skn-1a/c variants. The skn-1(zj0015) allele reduces detoxification gene expression and stress resistance to levels comparable to skn-1 RNAi, but unlike RNAi, it is not restricted from some tissues. We also show that skn-1(zj0015) is epistatic to canonical upstream regulators demonstrating its utility for genetic analysis of skn-1 function and regulation in cases where large numbers of worms are needed, a balancer is problematic, diet is varied, or RNAi cannot be used.
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    • "Also, studies have shown that loss-of-function mutations in daf-2 increases worms' lifespan (Kenyon et al., 1993;Kimura et al., 1997). This is partly because the disruption of DAF-2 releases the transcription factor DAF-16 to the nucleus allowing for increased expression of many genes related to resilience (Kimura et al., 1997;Hsu et al., 2003;Samuelson et al., 2007;Tullet et al., 2008;Kenyon, 2010b). In addition to DAF-16, other transcription factors have their function modified by DAF-2, such as SKN-1, HSF-1 and PQN-1 (Kimura et al., 1997;Hsu et al., 2003;Samuelson et al., 2007;Kenyon, 2010b;Bansal et al., 2014). "
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    • "Two conserved signaling pathways known to increase lifespan have been characterized in C. elegans (Cohen et al., 2006; Kenyon, 2005; Leavy, 2011; Murshid et al., 2013; Tissenbaum, 2012); one involves disruption of the insulin/IGF-1 receptor, DAF-2 (abnormal Dauer formation-2) signaling pathway, while the other involves activation of the NAD + dependent histone deacetylase SIR-2.1. C. elegans loss-of-function mutations in daf-2 have an extended lifespan, which is dependent on the activation of the transcription factor DAF-16 (homologous to human FOXO genes) (Apfeld and Kenyon, 1998; Gems et al., 1998; Tullet et al., 2008). Dietary restriction is one of the most consistent methods for producing lifespan extension in model organisms, activates DAF-16 through a decrease in PI3K/AKT signaling (Weinkove et al., 2006). "
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