title: The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
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.
authors: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors: Gizem
authors: G
authors: Rizki
authors: Terri Naoko
authors: TN
authors: Iwata
authors: Ji
authors: J
authors: Li
authors: Christian G
authors: CG
authors: Riedel
authors: Colette Lafontaine
authors: CL
authors: Picard
authors: Max
authors: M
authors: Jan
authors: Coleen T
authors: CT
authors: Murphy
authors: Siu Sylvia
authors: SS
authors: Lee
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D051863:Host Cell Factor C1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008136:Longevity / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D029742:Caenorhabditis elegans Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D034741:RNA, Small Interfering; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C497691:hcf-1 protein, C elegans; C507014:SIR-2.1 protein, C elegans; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins