Molecular Mechanisms For Neural Adhesion Molecules Of SHN-1 And NLG-1 In The Regulation Of Innate Immune Response In Caenorhabditis Elegans

Caenorhabditis elegans has been widely utilized as a model for the study of innate immunity.Candida albicans is considered to be the most common pathogenic fungus,and C.albicans can invade the host tissue and cause life-threatening infections,when the host immunity is reduced.Shank protein is a scaffold protein,and its homologous gene is shn-1 in C.elegans.Neuroligin is a postsynaptic protein,and its homologous gene is nlg-1 in C.elegans.However,the function of SHN-1 and NLG-1 in the regulation of innate immune response to fungal infection and the underlying molecular mechanism are still unclear.This study focused on the functions and the underlying molecular mechanism for the involvement of neural adhesion molecule of SHN-1 and NLG-1 in the regulation of innate immune response to fungal infection.shn-1 mutation increased the susceptibility of C.elegans to C.albicans SC5314 infection,and inhibited the innate immune response to fungal infection.The expression SHN-1::GFP was significantly up-regulated after C.albicans SC5314 infection for 24h.SHN-1 acted in both the intestine and the neurons to regulate the innate immune response to C.albicans SC5314 infection.The downstream target of neuronal SHN-1 was identified as GLR-1(an AMPA-type glutamate receptor)during the control of innate immune response to fungal infection.The downstream target of GLR-1 was further identified as DAT-1?SER-7 during the control of innate immune response to fungal infection.The downstream target of intestinal SHN-1 was identified as MGL-2(a metabotropic glutamate receptor)during the control of innate immune response to fungal infection.MGL-2 further regulated the innate immune response to C.albicans SC5314 infection by mediating the insulin signaling.Moreover,intestinal SHN-1 regulated the innate immune response to C.albicans SC5314 infection through the p38 MAPK signaling.nlg-1 mutation increased the susceptibility of C.elegans to C.albicans SC5314 infection,and suppressed the innate immune response to fungal infection.After C.albicans SC5314 infection for 24h,NLG-1::GFP expressed in neurons was significantly increased.NLG-1 acted in the neurons to play an important function in regulating the innate immune response to C.albicans SC5314 infection.The downstream target of NLG-1 was identified as MAGI-1(a tight junction protein containing multiple PDZ domains)during the control of innate immune response to fungal infection,and the downstream target of MAGI-1 was further identified as PKC-1 during the control of innate immune response to fungal infection.Additionally,NLG-1 could act downstream of SKN-lb in the neurons to regulate the innate immunity.In conclusion,our study revealed the important functions of SHN-1 and NLG-1 in regulating the innate immune response to fungal infection in C.elegans.Furthermore,the identified signaling cascade and the tissue-specific activities of SHN-1 and NLG-1 in the regulation of innate immune response will deepen our understanding the molecular mechanisms of innate immune response to fungal infection.