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

Abstract

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...

GATA Proteins Work Together with Friend of GATA (FOG) and C-terminal Binding Protein (CTBP) Co-regulators to Control Adipogenesis

“…Worms possessing a mutant form of ctbp-1 display an extension of life span, which can be suppressed by the reintroduction of ctbp-1. The function of ctbp-1 in life span control in C. elegans is dependent on its NAD ϩ / NADH binding activity (39). CTBP proteins can bind to NAD ϩ /NADH dinucleotides at concentrations comparable with those present within the cell (17).…”

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“…Nevertheless, both studies identify age-dependent alterations in the expression of select modifiers of chromatin state (Rossi et al, 2005;Chambers et al, 2007). Interestingly, chromatin modifiers have recently been found to control longevity in model organisms such as yeast, flies and worms Chen et al, 2009;Dang et al, 2009;Greer et al, 2010;Siebold et al, 2010). In addition, chromatin modifiers have been implicated in the control of a number of cellular processes that may contribute to longevity, including DNA damage repair, telomere maintenance and cellular metabolism (Vidanes et al, 2005;Longo and Kennedy, 2006;Blasco, 2007).…”

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“…Interestingly, a number of recent studies have reported that genes promoting lipolysis or fatty acid desaturation also promote longevity (11,19,33,55). Potentially, this could reflect altered energy metabolism, or changes to lipid composition, membrane fluidity, and signaling pathways (10,11).…”

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