CBP-1/p300 acetyltransferase regulates SKN-1/Nrf cellular levels, nuclear localization, and activity in C. elegans

Ganner, Athina; Gerber, Julia; Ziegler, A.; Li, Yujie; Kandzia, Jakob; Matulenski, Tanja; Kreis, Saskia; Breves, Gerhard; Klein, Marinella; Walz, Gerd; Neumann-Haefelin, Elke

doi:10.1016/j.exger.2019.110690

Cited by 21 publications

(14 citation statements)

References 46 publications

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“…Titration of SKN-1 expression is important for the pro-longevity nature of this transcription factor. Moderate overexpression of SKN-1 or mutation of the negative regulator wdr-23 extends the lifespan of C. elegans, while hypomorphic mutants or worms treated with skn-1 RNAi exhibit a shortened lifespan ( Grushko et al., 2021 ; Ganner et al., 2019 ; Tullet et al., 2008 , 2017 ; Tang and Choe, 2015 ). However, gain-of-function animals with constitutive expression of SKN-1 and animals containing high-copy arrays of SKN-1 exhibit a mild decrease in lifespan ( Paek et al., 2012 ; Tullet et al., 2008 ).…”

Section: Discussionmentioning

confidence: 99%

SKN-1 regulates stress resistance downstream of amino catabolism pathways

et al. 2022

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Section: Discussionmentioning

confidence: 99%

SKN-1 regulates stress resistance downstream of amino catabolism pathways

et al. 2022

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“…This was unexpected, as activating the HSR generally protects from aging ( Hsu et al, 2003 ; Morley and Morimoto, 2004 ). Since CBP-1 plays a positive role in a variety of physiological pathways that control aging ( Zhang et al, 2009 ; Cai et al, 2019 ; Ganner et al, 2019 ; Zhou et al, 2019 ; Li et al, 2021 ) it may be that the effects on these pathways are overriding the effects of CBP on HSF-1 and HSP expression in terms of life span regulation. It will be informative in future work to determine how the regulation of HSF-1 activity by CBP-1 can benefit aging and potentially lifespan in the worm.…”

Section: Discussionmentioning

confidence: 99%

The CBP-1/p300 Lysine Acetyltransferase Regulates the Heat Shock Response in C. elegans

Barrett

2022

Front. Aging

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The decline of proteostasis is a hallmark of aging that is, in part, affected by the dysregulation of the heat shock response (HSR), a highly conserved cellular response to proteotoxic stress in the cell. The heat shock transcription factor HSF-1 is well-studied as a key regulator of proteostasis, but mechanisms that could be used to modulate HSF-1 function to enhance proteostasis during aging are largely unknown. In this study, we examined lysine acetyltransferase regulation of the HSR and HSF-1 in C. elegans. We performed an RNA interference screen of lysine acetyltransferases and examined mRNA expression of the heat-shock inducible gene hsp-16.2, a widely used marker for HSR activation. From this screen, we identified one acetyltransferase, CBP-1, the C. elegans homolog of mammalian CREB-binding protein CBP/p300, as a negative regulator of the HSR. We found that while knockdown of CBP-1 decreases the overall lifespan of the worm, it also enhances heat shock protein production upon heat shock and increases thermotolerance of the worm in an HSF-1 dependent manner. Similarly, we examined a hallmark of HSF-1 activation, the formation of nuclear stress bodies (nSBs). In analyzing the recovery rate of nSBs, we found that knockdown of CBP-1 enhanced the recovery and resolution of nSBs after stress. Collectively, our studies demonstrate a role of CBP-1 as a negative regulator of HSF-1 activity and its physiological effects at the organismal level upon stress.

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“…Titration of SKN-1 expression is important for the pro-longevity nature of this transcription factor. Moderate overexpression of SKN-1 or mutation of the negative regulator wdr-23 extends the lifespan of C. elegans , while hypomorphic mutants or worms treated with skn-1 RNAi exhibit a shortened lifespan (Grushko et al, 2021; Ganner et al, 2019; Tullet et al, 2017; Tang and Choe, 2015; Tullet et al, 2008). However, gain-of-function animals with constitutive expression of SKN-1 and animals containing high-copy arrays of SKN-1 exhibit a mild decrease in lifespan (Paek et al, 2012; Tullet et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance

Frankino

Siddiqi

Bolas

et al. 2022

Preprint

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The deleterious potential to generate oxidative stress and damage is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and physiological consequences of this remain unknown. To explore this connection, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that genetic perturbation of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated detoxification genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires the GATA transcription factor ELT-3, nuclear hormone receptor NHR-49, and mediator complex subunit MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate (IP). Triggering SKN-1 activation results in a physiological trade off of increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 is a key surveillance factor which senses and responds to metabolic perturbations to influence physiology and stress resistance.

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CBP-1/p300 acetyltransferase regulates SKN-1/Nrf cellular levels, nuclear localization, and activity in C. elegans

Cited by 21 publications

References 46 publications

SKN-1 regulates stress resistance downstream of amino catabolism pathways

SKN-1 regulates stress resistance downstream of amino catabolism pathways

The CBP-1/p300 Lysine Acetyltransferase Regulates the Heat Shock Response in C. elegans

SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance

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