The Function And Mechanism Study Of KISS1 Receptor GPR54 In Antiviral Innate Immune Responses

Type I interferons play very important roles in antiviral innate immune responses.During viral infection,the pattern recognition receptors(PRRs)of host detect the invasion of viruses and then trigger the activation of a series of downstream signaling molecules to initiate the secretion of type I interferons and a large number of inflammatory cytokines.Type I interferons bind to cell surface receptors in an autocrine or paracrine manner and induce the expression of hundreds of interferon-stimulated genes(ISGs).These ISGs could interfere with viral replication at different stages or in different manner.In recent years,arounding the regulation of type I interferons signaling pathways,the scientists conducted extensive research,however,the regulation of type I interferons signaling pathways are intricate,these studies are far from satisfactory and still need to be further investigated.With nearly 1000 members,G protein-coupled receptors(GPCRs)constitute the largest group of cell surface proteins.Since they are almost involved in all major physiological and pathological processes of the body,they have become a top priority in the field of new drug discovery.In recent years,more and more studies have shown that GPCRs are closely related to viral infection,therefore,it is possible to further explore the relationship between GPCRs and viral infection,especially the relationship between GPCRs and the regulation of interferons signaling pathways,which may provide new ideas for the treatment of viral diseases.As an important neuropeptide hormone receptor,GPR54 not only plays an essential role in regulating the development of puberty,but also inhibits the metastasis of tumor cells under the role of endogenous ligand KISS1.Although there are considerable evidences that the central nervous system and the endocrine system play important roles in regulating the immune system,the regulation on the immune function of KISS1/GPR54 system has not been reported.Here,we found that KISS1/GPR54 system could modulate antiviral innate immune responses by regulating phosphatase Calcineurin activity.First,we found that viral infection significantly increased the expression of GPR54 ligand KISS1 in the hypothalamus and pituitary gland of mice,suggesting that the KISS1/GPR54 system was likely to be involved in viral infection.Further study found that in GPR54-deficient macrophages,Virus-induced IFN-? expression was significantly improved compared to wild-type macrophages,meanwhile the replication of viruses were significantly reduced.Similar data was also observed in GPR54-deficient mice.Accordingly,when we expressed GPR54 in the HEK-293T,Virus-induced the production of IFN-? was dramatically impaired and the replication of viruses were significantly increased.Further studies found that viral infection significantly increased the secretion of Kisspeptins in mouse serum,as a natural ligand of GPR54,Kisspeptin-10(KP-10)significantly inhibited the virus-induced IFN-P production.Interestingly,we found that GPR54 ligand KISS1 was not expressed in macrophages,suggesting that KISS1 is likely to regulate the type ? interferons in a paracrine manner.Mechanismsly,we found that activated GPR54 could recruit phosphatase Calcineurin through the carboxyl terminal PRR motif and increase its phosphatase activity through a calcium ions dependent manner,Calcineurin targets the key kinase TBK1 in type ?interferons signaling pathways and makes it dephosphorylated and inactivated,which in turn limits type ? interferons production.Taken together,our study revealed that the KISS1/GPR54 system plays an important role in negative feedback regulation of type? interferons signaling pathways,KISS1/GPR54 and Calcineurin may serve as important targets for the treatment of viral diseases.At the same time,our study also shown that the central nervous system could modulate the antiviral innate immune responses through the KISS 1/GPR54 signaling,it helps to understand the complex regulatory relationship between the central nervous system and the immune system.In addition,this study also provided a reference for the crosstalk of more GPCRs and antiviral innate immune responses in the future.