RLE-1, an E3 Ubiquitin Ligase, Regulates C. elegans Aging by Catalyzing DAF-16 Polyubiquitination

Li, Wensheng; Gao, Beixue; Lee, Sang Myeong; Bennett, Karen; Fang, Deyu

doi:10.1016/j.devcel.2006.12.002

Cited by 113 publications

(108 citation statements)

References 44 publications

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“…2B and D). This Ϸ20% change in life span is in line with the recent reports of a number of genes whose de-regulation also resulted in a similar increase of life spans (17,18).…”

Section: Resultssupporting

confidence: 78%

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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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“…2B and D). This Ϸ20% change in life span is in line with the recent reports of a number of genes whose de-regulation also resulted in a similar increase of life spans (17,18).…”

Section: Resultssupporting

confidence: 78%

“…2B and D). This Ϸ20% change in life span is in line with the recent reports of a number of genes whose de-regulation also resulted in a similar increase of life spans (17,18).Several lines of evidence further support the notion that the life span extension phenotype is caused by the loss of ctbp-1. First, depletion of ctbp-1 by RNAi (Fig.…”

supporting

confidence: 74%

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 discovery of an E3 ubiquitin ligase working through DAF16 (Li et al 2007) precipitated a thorough evaluation of the involvement of Cullin and SKR (Skp-1 related) genes in lifespan determination (Ghazi et al 2007). Although RNAi targeting of all of the Cullins and most of the SKR genes had no effect on wild-type animals' lifespan, we found that 8/21 SKR genes are significantly down-regulated during the transition to state II.…”

Section: Molecular Basis For Morphological Age Statesmentioning

confidence: 99%

Molecular characterization of the transition to mid-life in Caenorhabditis elegans

Eckley

Rahimi

Mantilla

et al. 2012

AGE

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We present an initial molecular characterization of a morphological transition between two early aging states. In previous work, an age score reflecting physiological age was developed using a machine classifier trained on images of worm populations at fixed chronological ages throughout their lifespan. The distribution of age scores identified three stable post-developmental states and transitions. The first transition occurs at day 5 post-hatching, where a significant percentage of the population exists in both state I and state II. The temperature dependence of the timing of this transition (Q 10~1 .17) is too low to be explained by a stepwise process with an enzymatic or chemical rate-limiting step, potentially implicating a more complex mechanism. Individual animals at day 5 were sorted into state I and state II groups using the machine classifier and analyzed by microarray expression profiling. Despite being isogenic, grown for the same amount of time, and indistinguishable by eye, these two morphological states were confirmed to be molecularly distinct by hierarchical clustering and principal component analysis of the microarray results. These molecular differences suggest that pharynx morphology reflects the aging state of the whole organism. Our expression profiling yielded a gene set that showed significant overlap with those from three previous age-related studies and identified several genes not previously implicated in aging. A highly represented group of genes unique to this study is involved in targeted ubiquitin-mediated proteolysis, including Skp1-related (SKR), F-box-containing, and BTB motif adaptors.

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“…While this study was in press, Li et al (39) published results identifying an E3 ligase that affects aging in an opposite fashion. …”

mentioning

confidence: 99%

Regulation of Caenorhabditis elegans lifespan by a proteasomal E3 ligase complex

Ghazi

Henis-Korenblit

Kenyon

2007

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

120

102

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The proteasome maintains cellular homeostasis by degrading oxidized and damaged proteins, a function known to be impaired during aging. The proteasome also acts in a regulatory capacity through E3 ligases to mediate the spatially and temporally controlled breakdown of specific proteins that impact biological processes. We have identified components of a Skp1-Cul1-F-Box E3 ligase complex that are required for the extended lifespan of Caenorhabditis elegans insulin/insulin-like growth factor-1-signaling (IIS) mutants. The CUL-1 complex functions in postmitotic, adult somatic tissues of IIS mutants to enhance longevity. Reducing IIS function leads to the nuclear accumulation of the DAF-16/FOXO transcription factor, which extends lifespan by regulating downstream longevity genes. These CUL-1 complex genes act, at least in part, by promoting the transcriptional activity of DAF-16/FOXO. Together, our findings describe a role for an important cellular pathway, the proteasomal pathway, in the genetic determination of lifespan.aging ͉ proteasome ͉ ubiquitin ͉ daf-2 ͉ insulin

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RLE-1, an E3 Ubiquitin Ligase, Regulates C. elegans Aging by Catalyzing DAF-16 Polyubiquitination

Cited by 113 publications

References 44 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

Molecular characterization of the transition to mid-life in Caenorhabditis elegans

Regulation of Caenorhabditis elegans lifespan by a proteasomal E3 ligase complex

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