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

Shuzhen Chen, Johnathan R. Whetstine, Salil Ghosh, John A. Hanover, Reddy R. Gali, Paul Grosu, Yang Shi

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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 deacety- lase 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.

Original languageEnglish
Pages (from-to)1496-1501
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number5
DOIs
StatePublished - Feb 3 2009
Externally publishedYes

Keywords

  • Aging
  • CtBP
  • Transcription corepressor

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