The Nuclear RNAi Pathway Regulates DAF-16/FOXO to ControlC. elegansLongevity andDauerEntry

Abstract

ABSTRACTCaenorhabditis eleganswith impaired insulin/IGF-1 receptor signalling (IIS) or with germline ablation live longer and this phenomenon is entirely dependent on the transcription factor DAF-16 - theC. eleganshomolog of the class O of the forkhead box transcription factors (FoxO). In a candidate RNAi screen designed to search for new modifiers of DAF-16 function among genes involved in histone modification and/or small RNA-mediated silencing pathways, we foundnrde-1, wago-1, andadr-1as positive regulators of DAF-16. We confirmed by several methods and in different models that DAF-16 translocation to the nucleus and, subsequently, its function is tightly controlled by these genes and narrowed down to components of the NRDE complex and the nuclear RNAi pathway as key DAF-16 modulators. Importantly, we found that the NRDE pathway controls DAF-16-mediated longevity anddauerentry. Our epistasis data indicate thatnrde-1interacts withakt-1to control lifespan. We also demonstrated that NRDE-1 acts downstream of AGE-1/PI3K and partially requires mTORC2 and AKT-1 to control DAF-16 translocation. These results unveil a mechanism of regulation ofdauerformation and longevity inC. elegansvia nuclear RNAi-mediated modulation of DAF-16 function in a manner that involves the mTORC2-AKT axis.