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

TitleThe evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
Publication TypeJournal Article
Year of Publication2011
AuthorsRizki G, Iwata TNaoko, Li J, Riedel CG, Picard CLafontaine, Jan M, Murphy CT, Lee SSylvia
JournalPLoS Genet
Volume7
Issue9
Paginatione1002235
Date Published2011 Sep
ISSN1553-7404
KeywordsAnimals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Evolution, Molecular, Forkhead Box Protein O3, Forkhead Transcription Factors, HEK293 Cells, Host Cell Factor C1, Humans, Longevity, RNA, Small Interfering, Signal Transduction, Sirtuin 1, Sirtuins, Stress, Physiological, Transcription Factors, Transcription, Genetic
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.

DOI10.1371/journal.pgen.1002235
Alternate JournalPLoS Genet.
PubMed ID21909281
PubMed Central IDPMC3164695
Grant ListR01 AG024425 / AG / NIA NIH HHS / United States
AG024425 / AG / NIA NIH HHS / United States
R56 AG024425 / AG / NIA NIH HHS / United States
R01 AG034446 / AG / NIA NIH HHS / United States
T32 HD052471 / HD / NICHD NIH HHS / United States
T32HD052471 / HD / NICHD NIH HHS / United States