RESUMEN
Host cell factor-1 (HCF-1) is a conserved regulator of the longevity and stress response functions of DAF-16/FOXO. SKN-1 transcription factor is an evolutionarily conserved xenobiotic stress regulator and a pro-longevity factor. Here, we demonstrate that SKN-1 contributes to the enhanced oxidative stress resistance incurred by hcf-1 mutation in C. elegans. HCF-1 prevents the nuclear accumulation of SKN-1 and represses the transcriptional activation of SKN-1 specifically at target genes involved in cellular detoxification pathways. Our findings reveal a novel and context-specific regulatory relationship between two highly conserved longevity and stress response factors HCF-1 and SKN-1.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Unión al ADN/metabolismo , Factor C1 de la Célula Huésped/metabolismo , Factores de Transcripción/metabolismo , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/genética , Genes de Helminto , Factor C1 de la Célula Huésped/genética , Longevidad/genética , Longevidad/fisiología , Mutación , Estrés Oxidativo , Factores de Transcripción/genéticaRESUMEN
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.