Caenorhabditis elegans HCF-1 Functions in Longevity Maintenance as a DAF-16 Regulator

Abstract

The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.

DAF-16/Forkhead Box O Transcription Factor: Many Paths to a Single Fork(head) in the Road

“…A number of additional cofactors have been identified that either positively or negatively regulate DAF-16 activity. The C. elegans host-cell factor homolog host cell factor 1 (HCF-1) interacts with and inhibits DAF-16 transcriptional activity in the nucleus (62). Consistent with this, knockdown of hcf-1 by RNAi results in increased lifespan (62).…”

“…The C. elegans host-cell factor homolog host cell factor 1 (HCF-1) interacts with and inhibits DAF-16 transcriptional activity in the nucleus (62). Consistent with this, knockdown of hcf-1 by RNAi results in increased lifespan (62). In addition, the Wnt signalling pathway has been found to intersect with IIS at the level of DAF-16=FOXO, where the worm homolog of beta-catenin (BAR-1) interacts with DAF-16 required for the transcription of oxidative stress-related genes (22).…”

E2F Transcription Factor 1 Regulates Cellular and Organismal Senescence by Inhibiting Forkhead Box O Transcription Factors

“…As our data show that E2F1 directly binds to the C-terminal transcription-activation domain of FOXO3, we postulate that it acts by blocking its ability to transcriptionally activate certain FOXO3 target genes such as MnSOD and catalase. This mode of regulation by E2F1 is reminiscent to HCF-1, the C. elegans homolog of mammalian host cell factor 1, which directly binds to DAF-16 in the nucleus and negatively regulates DAF-16, possibly by preventing DAF-16 from binding to the promoters of its target genes (33).…”

The Role of Transcription Factors Dfoxo, Dsir2 and Hsp70 in Lifespan Alteration of Drosophila Melanogaster in Different Light Conditions

“…Гены сиртуинов играют ключевую роль в регуляции скорости старения и долголетия. В частности, повсеместное подавление экс-прессии dSir2 и двух dSir2-подобных генов (CG5085 и CG6284) методом интерференции РНК в нейронах дро-зофил снижает ПЖ, а увеличение активности сиртуинов у дрожжей, червей или мух значительно продлевает ПЖ (Kusama et al, 2006;Li et al, 2008;Niedernhofer et al, 2008;Russell, Kahn, 2007). Существенное снижение МеПЖ на свету происходит и у линий с мутациями в генах семейства Hsp70.…”