ERK signaling licenses SKN-1A/NRF1 for proteasome production and proteasomal stress resistance

Zhang, Peng; Qu, Haiyan; Wu, Ziyun; Na, Huimin; Hourihan, John M.; Zhang, Fang; Zhu, Feimei; Isik, Meltem; Walhout, Albertha J.M.; Feng, Yuxiong; Blackwell, T. Keith

doi:10.1101/2021.01.04.425272

Cited by 5 publications

(4 citation statements)

References 76 publications

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“…We wanted to determine if impairment of proteasome function can induce the oomycete recognition response (ORR). We performed RNAseq analysis of ddi-1(icb156) mutants versus wild-type controls and compared the set of up-regulated genes with those previously reported for inhibition of proteasomal activity by BTZ drug treatment [35], oomycete recognition response [3] and skn-1a loss-of-function [35]. A significant overlap was identified between all these datasets (Figure 1D, S1B, and supplementary table S1).…”

Section: Mutants In the Proteasome Surveillance Pathway Show Constitu...mentioning

confidence: 79%

Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens inC. elegans

Grover,

Gang,

Troemel

et al. 2023

Preprint

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Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF upregulates proteostasis capacity after blockade of the proteasome, and also promotes resistance against bacterial infection in the nematode C. elegans. SKN-1/NRF has three isoforms, and the SKN-1A/NRF1 isoform in particular regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1, show constitutive expression of immune response programmes against natural eukaryotic pathogens of C. elegans. These programmes are the Oomycete Recognition Response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the Intracellular Pathogen Response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programmes are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner, against natural eukaryotic pathogens of the C. elegans epidermis and intestine.

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Section: Mutants In the Proteasome Surveillance Pathway Show Constitu...mentioning

confidence: 79%

Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens inC. elegans

Grover,

Gang,

Troemel

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…If this were the case, then induction would not be affected by proteasome impairment via bortezomib (BTZ) drug treatment [ 35 ]. To determine if impairment of proteasome function can induce the ORR, we performed RNAseq analysis of ddi-1(icb156) mutants versus wild-type controls and compared the set of up-regulated genes with those previously reported for inhibition of proteasomal activity by BTZ drug treatment [ 36 ], oomycete recognition response [ 3 ], and skn-1a loss-of-function [ 36 ]. A significant overlap was identified between all these datasets (Figs 1C and S1C , and S1 Table ).…”

Section: Resultsmentioning

confidence: 99%

Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans

Grover,

Gang,

Troemel

et al. 2024

PLoS Biol

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Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF up-regulates proteostasis capacity after blockade of the proteasome and also promotes resistance against bacterial infection in the nematode Caenorhabditis elegans. SKN-1/NRF has 3 isoforms, and the SKN-1A/NRF1 isoform, in particular, regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1 show constitutive expression of immune response programs against natural eukaryotic pathogens of C. elegans. These programs are the oomycete recognition response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the intracellular pathogen response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programs are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner against natural eukaryotic pathogens of the C. elegans epidermis and intestine.

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“…Dysfunction of this TF is associated with glucose metabolism reprogramming via AMPK signaling (Yang et al, 2021). NFE2L1 also upregulates expression of proteasomal genes in an ERK-signaling dependent manner (Zhang et al, 2021b), which is suggested to contribute to the development of neurodegenerative diseases (Lee et al, 2011).…”

Section: Supplementary Informationmentioning

confidence: 99%

Breakdown and repair of the aging brain metabolic system

Shichkova,

Coggan,

Kanari

et al. 2023

Preprint

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Cognitive impairments and neurodegeneration in aging are linked to disrupted brain energy metabolism. We address this experimentally challenging problem with a computational molecular model that provides mechanistic insights and therapeutic predictions. This model encompasses key enzymes, transporters, metabolites, and other important factors, enabling the investigation of over 66,000 molecular interactions within and across cellular and subcellular compartments of neurons, glia, and blood vessels. During aging, action potential generation is primarily impaired due to reduced expression of the Na+/K+-ATPase pump and diminished ATP supply. The metabolic system loses flexibility, hindering its ability to effectively respond to stimuli or adapt to molecular damage. Astrocytes may defer to neuronal energy stability at their own expense. We identified potential strategies for rejuvenating the aged brain including supplying nutritional factors to the blood, increasing the NADH cytosol-mitochondria shuttle capacity and the expression of Na+/K+-ATPase. Transcription factor analysis implicated the estrogen related receptor alpha (ESRRA) as having the highest potential impact on aging, suggesting that dysregulated energy metabolism may be a transitional state between healthy aging and neurodegenerative disorders, rather than a hallmark of aging. This high-fidelity model serves as a foundation for future research on aging and cognitive health.

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ERK signaling licenses SKN-1A/NRF1 for proteasome production and proteasomal stress resistance

Cited by 5 publications

References 76 publications

Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens inC. elegans

Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens inC. elegans

Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans

Breakdown and repair of the aging brain metabolic system

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