Transcription Factor ZIP-11 Is Involved In The Regulation Of Innate Immunity In Caenorhabditis Elegans

Innate immunity is the first line of host defence against pathogens in metazoans.Many diseases are associated with immune disorders and the homeostasis of the immune system is the basis of biological process.From an evolutionary point,innate immunity is conserved.The study of regulatory mechanisms of innate immunity plays an important role in understanding the relationship between human autoimmune diseases and pathogenic bacteria and hosts.In this study,Caenorhabditis elegans was used as a model organism to study the innate immune regulation mechanism of nematodes infected with human opportunistic pathogen Pseudomonas Aeruginosa PA14.In order to discover new immune regulatory factors,wild-type nematodes were fed OP50 and PA14 for 24 h,respectively,and transcriptome sequencing was performed.The results showed that a b ZIP transcription factor ZIP-11 of m RNA was significantly up-regulated in PA14 group compared with OP50 group.Basic leucine zip structure(b ZIP)factor is a key regulatory factor involved in vital cell activities,such as immune cell differentiation,cell cancer regulation and other processes.We construct the transgenic C.elegans strain ZIP-11::GFP and imaged 24 h after PA14 infection.The imaging results showed that the expression level of transcription factor ZIP-11::GFP was up-regulated and the entry of transcription factor into the nucleus was significantly enhanced after PA14 infection.To test if ZIP-11 acts in innate immune response,we first examined the survival of ZIP-11 defificient worms upon P.aeruginosa PA14 infection.We found that zip-11(tm4554)null mutant worms exhibited reduced resistance to killing by P.aeruginosa PA14 as compared to wild-type.The result of zip-11 RNAi experiment is in accord with zip-11(tm4554)mutants.Based on this,we conducted tissue-specific interference experiments,and the results showed that only intestinal tissue-specific interference ZIP-11 could weaken the C.elegans’ s resistannce to PA14.Genetic pathway screening experiment results show that transcription factor ZIP-11 regulates innate immunity of C.elegans by participating in the conserved immune signaling pathway PMK-1/ P38.Interestingly,we also found that transcription factor ZIP-11 has a feedback regulatory process with protein kinase PMK-1.In addition,we found that transcription factor ZIP-11 can also bind to CEBP-2,which is involved in immune regulation independent of PMK-1,such as IRG-1,to exert immune function.Finally,we demonstrated that the human homolog ATF4 of ZP-11 could substitute for the immune function of ZP-11 in C.elegans.Our study reveal that transcription factor ZIP-11 is a novel regulator of the innate immune response of C.elegans.Moreover,b ZIP transcription factor is conserved in evolution and function,and human homologous protein ATF4 in human functionally substitute for zip-11.However,its role in human immune regulation needs further study.