International Worm Meeting,
Here we investigated how cholesterol influences the Insulin/IGF-1 signaling (IIS) pathway in Caenorhabditis elegans. Cholesterol affects many IIS functions, including dauer formation rate, oxidative stress resistance, fat storage, and longevity. Moreover, DAF-16 transcriptional activity in IIS is also modulated by cholesterol. These responses are mediated by a novel protein called nematode sterol binding protein (NSBP)-1, which is a homolog of human nucleosome assembly protein 1 encoded by D2096.8. NSBP-1 is expressed at sites of cholesterol accumulation and translocates to the nucleus independent of DAF-16 in response to IIS. Site-directed mutagenesis revealed possible NSBP-1 phosphorylation at Thr203. Co-immunoprecipitation studies demonstrated that NSBP-1 associates with DAF-16 and that this interaction can be affected by cholesterol concentration. Experiments using RNAi against NSBP-1 and DAF-16 demonstrated that these proteins work together to regulate the effects of cholesterol on the IIS pathway, as well as cholesterol homeostasis, in C. elegans. Our results may be applicable to screening of novel therapeutic targets for ameliorating insulin-resistant diabetes which can be caused by hyperactivation of FOXO in mammals.