Activation Mechanism Of C.elegans Transcription Factor HLH-30 In Adversity

The mammalian transcription factor EB(TFEB)is an important transcription factor,which is crucial to many physiological processes in organism.In a state of starvation,TFEB controls transcription of autophagy genes and lysosomal biosynthesis genes.In the state of adequate nutrition,TFEB is negatively regulated by the upstream kinase mTORC1 and ERK2,so that TFEB is in an inhibitory state.Moreover,in the absence of nutrition,TFEB can regulate lipid mobilization.For lysosomal and protein aggregation disorders,enhancing TFEB activity may be an effective treatment.TFEB is rapidly activated in mice macrophages upon Staphylococcus aureus infection and required for induction of several proinflammatory cytokines.Therefore,TFEB is considered to be an important host defense factor.In C.elegans,TFEB homolog HLH-30 regulates autophagy,and plays an important role in a variety of longevity models,nuclear localization of HLH-30 is increased in different longevity model,and overexpression of HLH-30 extends lifespan.HLH-30 is also critical for host defense.HLH-30 was activated shortly after S.aureus infection,and drive the expression of close to 80%of the host response genes,including antimicrobial and autophagy genes.In the natural world,pathogenic microorganisms,crowding,and formation of diapause in adverse environment(high temperature)are potential adversities for C.elegans In this paper,we studied the effects of these stress conditions on HLH-30.We demonstrated that HLH-30 was activated shortly after S.aureus infection,which was independent of DAF-9/DAF-12 signaling pathway.HLH-30 was not translocated to nucleus after the infection with S.aureus and P.aeruginosa of 12 hours,we suspect that the temperature may inhibit the HLH-30 entry into the nucleus,which is due to a temperature of 25?,this result suggests that HLH-30 is very sensitive to temperature and infection time.We demonstrated that S.aureus could activate HLH-30 through the NHR-49/FAT-7/NHR-80 signaling pathway in a short time.HLH-30 was translocated into the nucleus in crowded situation,which was independent of the NHR-49/FAT-7/NHR-80 and DAF-9/DAF-12 signaling pathway.We also demonstrated that compared with the L3 larva,during high temperature-induced dauer stage,HLH-30 nuclear translocation and expression were increased.Finally,we demonstrated that HLH-30 nuclear translocation was independent of hypoxia and pressure change.In summary,our study reveals the effects of stress on HLH-30 and its regulatory mechanism.