The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO

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. © 2011 rizki et al.