A survival pathway for<i>Caenorhabditis elegans</i>with a blocked unfolded protein response

Urano, Fumihiko; Calfon, Marcella A.; Yoneda, Takunari; Yun, Chi Young; Kiraly, Moni; Clark, Scott G.; Ron, David

doi:10.1083/jcb.200203086

Cited by 191 publications

(198 citation statements)

References 28 publications

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“…In fact, some of the CTBP-1 target genes have already been shown to affect the aging process in other studies. For instance, we identified up-regulation of genes such as ABU (activated in blocked unfolded protein response) and PQN (prion-like Q/N proteins) involved in the ER stress response (35). The ER stress response is important to maintain protein homeostasis and has been implicated in different forms of stress response (36,37).…”

Section: Resultsmentioning

confidence: 95%

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

Chen

Whetstine²,

Ghosh³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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CtBP (C-terminal binding protein) is an evolutionarily conserved NAD(H)-dependent transcriptional corepressor, whose activity has been shown to be regulated by the NAD/NADH ratio. Although recent studies have provided significant new insights into mechanisms by which CtBP regulates transcription, the biological function of CtBP remains incompletely understood. Here, we report that genetic inactivation of the Caenorhabditis elegans homolog, ctbp-1, results in life span extension, which is suppressed by reintroduction of the ctbp-1 genomic DNA encoding wild-type but not NAD(H)-binding defective CTBP-1 protein. We show that CTBP-1 possibly modulates aging through the insulin/IGF-1 signaling pathway, dependent on the forkhead transcription factor DAF-16, but independent of the NAD-dependent histone deacetylase SIR-2.1. Genome-wide microarray analysis identifies >200 potential CTBP-1 target genes. Importantly, RNAi inhibition of a putative triacylglycerol lipase gene lips-7(C09E8.2) but not another lipase suppresses the life span extension phenotype. Consistently, metabolic analysis shows that the triacylglycerol level is reduced in the ctbp-1 deletion mutant, which is restored to the wild-type level by RNAi inhibition of lips-7. Taken together, our data suggest that CTBP-1 controls life span probably through the regulation of lipid metabolism.aging ͉ CtBP ͉ transcription corepressor C tBP is a transcriptional corepressor that is evolutionarily conserved from Caenorhabditis elegans to human (1). CtBP shares sequence homology with the NAD/NADH-dependent 2-hydroxy acid dehydrogenases (2-Hacid DH) (2), and has been shown to exhibit dehydrogenase activity in vitro (3-5), although the physiological substrates and functional significance of this enzymatic activity remain unclear. CtBP binds NAD and NADH, and the NAD/NADH ratio appears to regulate the interactions of CtBP with DNA-binding transcription factors (6, 7), suggesting a potential role for CtBP as a sensor of cellular redox states. CtBP represses transcription by recruiting multiple histone modifying enzymes including the histone H3 lysine 9 (H3K9) methyltransferase G9a/HMTase1 and the histone H3 lysine 4 (H3K4) demethylase LSD1 (3,8). Previous studies suggest a role for CtBP in mouse development, apoptosis, and hypoxia-induced tumor migration (9-12). However, by and large, the biology of CtBP is still incompletely understood.Aging is a complex process regulated by an interacting network of factors. The insulin/insulin-like growth factor-1 (IGF-1) signaling pathway, the JNK anti-stress pathway and the mitochondria respiratory chain, have all been shown to regulate the aging process (13). Besides genetic factors, environmental conditions including stress and nutrient availability, have also been demonstrated to influence longevity (13-15). Transcription factors including DAF-16 and the NAD-dependent histone deacetylase SIR2 are at the converging points to integrate these different signals and regulate longevity through modulating gene transcription (13,15). Similar...

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Section: Resultsmentioning

confidence: 95%

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

Chen

Whetstine²,

Ghosh³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The observation that the PERK pathway is activated in mice that express aggregationprone PrP species directly links PrP toxicity and the UPR ER (Herrmann et al 2015). A fourth UPR ER pathway that is activated when the canonical mechanisms are blocked was identified in the nematode Caenorhabditis elegans (Urano et al 2002).…”

Section: T Dubnikov Et Almentioning

confidence: 99%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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“…In Caenorhabditis elegans, three proteins are known to sense ER stress and activate the UPR: the ribonuclease inositol-requiring protein-1 (IRE-1), the PERK kinase homologue PEK-1, and activating transcription factor-6 (ATF-6) (2)(3)(4)(5). Of the three, IRE-1 is the most conserved.…”

mentioning

confidence: 99%

“…When activated by ER stress, IRE-1's endonuclease activity is switched on, and it then removes an intron from xbp-1 (X-box binding protein-1) mRNA through unconventional splicing (2,4). Spliced xbp-1 encodes a transcription factor that activates expression of downstream genes, such as genes encoding chaperones and ER-associated degradation proteins (2,4,5), that expand the ER's folding capacity and increase degradation of misfolded proteins.…”

mentioning

confidence: 99%

Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity

Henis-Korenblit

Zhang²,

Hansen³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

215

181

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When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.aging | daf-2 | insulin signaling | unfolded protein response

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A survival pathway forCaenorhabditis eleganswith a blocked unfolded protein response

Cited by 191 publications

References 28 publications

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

Protein Quality Control in Health and Disease

Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity

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