Authors: Rizki G; Iwata TN; Li J; Riedel CG; Picard CL; Jan M; Murphy CT; Lee SS
Abstract: The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity determinant previously shown to act as a co-repressor of DAF-16. We report here that HCF-1 represents an integral player in the regulatory loop linking SIR-2.1/SIRT1 and DAF-16/FOXO in both worms and mammals. Genetic analyses showed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response in C. elegans. Gene expression profiling revealed a striking 80% overlap between the DAF-16 target genes responsive to hcf-1 mutation and sir-2.1 overexpression. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16-mediated transcription particularly important for aging and stress responses. Analogous to its role in regulating DAF-16/SIR-2.1 target genes in C. elegans, the mammalian HCF-1 also repressed the expression of several FOXO/SIRT1 target genes. Protein-protein association studies demonstrated that SIR-2.1/SIRT1 and HCF-1 form protein complexes in worms and mammalian cells, highlighting the conservation of their regulatory relationship. Our findings uncover a conserved interaction between the key longevity determinants SIR-2.1/SIRT1 and HCF-1, and they provide new insights into the complex regulation of FOXO proteins.
Keywords: Animals; Caenorhabditis elegans/genetics/physiology; Caenorhabditis elegans Proteins/genetics/metabolism; Evolution, Molecular; Forkhead Transcription Factors/genetics/*metabolism; HEK293 Cells; Host Cell Factor C1/genetics/*metabolism; Humans; Longevity/*genetics; RNA, Small Interfering/genetics; Signal Transduction; Sirtuin 1/genetics/*metabolism; Sirtuins/genetics/metabolism; Stress, Physiological/*genetics; Transcription Factors/genetics/metabolism; Transcription, Genetic|
Journal: PLoS genetics Volume: 7 Issue: 9 Pages: e1002235 Date: Sept. 13, 2011 PMID: 21909281 |
Rizki G, Iwata TN, Li J, Riedel CG, Picard CL, Jan M, Murphy CT, Lee SS (2011) The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS genetics 7: e1002235.
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