HIF-1? Functions As A Molecular Switch Connecting Bacterial And Iron Cues With Innate Immunity

Autophagy is a process that engulfs cytoplasmic proteins or organelles and coats them into vesicles,and fuses with lysosomes to form autophagy lysosomes,then degrades the contents they encapsulate.Cells use autophagy to dispose of wastes and eliminate hazards,while recycling nutrients and tuning metabolism in this process.Through these functions,autophagy promotes cell fitness,genome integrity,tissue homeostasis,cell survival and growth under stress.Autophagy plays a significant role in degrading the pathogenic bacterium Salmonella enterica serovar Typhimurium.Nutritional immunity is a process by which a host organism sequesters trace minerals,such as iron and zinc,in an effort to limit pathogenicity during infection.Iron is an essential metal for almost all living organisms and widely involved in a variety of fundamental physiological processes.In humans,the homeostasis of iron is tightly regulated to avoid cellular damage associated with iron overload or hypoferremia with iron deficiency by a complex mechanism.For instance,ferritin is believed to enhance the ability of host to compete with bacteria for iron,thereby inhibiting bacterial proliferation.However,the molecular mechanism by which the host modulates innate immunity against bacterial infections depending on available iron,a key nutritional cue,remains largely unknown.Using the human colon adenocarcinoma cell(Caco-2 cell)as models,we demonstrated that under normal conditions,S.Typhimurium induced autophagy in Caco-2 cells,which is required for resistance to S.Typhimurium infection.Supplementation with Ferric ammonium citrate(FAC)increased the accumulation of S.Typhimurium,which was due to inhibition of autophagy.Through screening of 45 signaling pathways,we found that hypoxia was activated after S.Typhimurium infection.Specifically,there are two lines of defense against pathogen regulated by hypoxia inducible factor-1?(HIF-1?)in Caco-2 cells.Under the conditions of S.Typhimurium infection,HIF-1? was translocated into nucleus,which was involved in resistance to S.Typhimurium infection.However,in the presence of FAC,HIF-1? was inactivated,leading to upregulation of Ferritin(FTH1)protein levels.FTH1,whichprobably functioned as an iron chelator,was crucial for resistance to S.Typhimurium infection in the presence of FAC.In conclusion,our study clarifies the regulatory mechanism of autophagy and ferritin FTH1 in host defense against S.Typhimurium infection.HIF-1? acts as a molecular switch linking iron available with host defense against pathogen infection by regulating levels of autophagy and ferritin FTH1.The current study reveals a novel pathway in nutritional immunity mediated by intestinal cells.