Molecular Basis For Let-7 In The Control Of Innate Immune Respones In Caenorhabditis Elegans

Once the pathogenic bacteria infect nematode, C. elegans usually responds to pathogen exposure by avoiding pathogens or activating an inducible innate immune system. Caenorhabditis elegans has become a classic model for the study of innate immunity because of its many advantages. microRNAs (miRNAs) were first found in C. elegans as a kind of very important molecular, and miRNAs exert their biology functions by suppressing the expression of targeted genes, let-7 is one of the important founding members of miRNAs identified in C. elegans. let-7 can act as a developmental switch to control the timing of the larval and adult transition. Previous study has further demonstrated that let-7 is involved in the control of innate immunity; however, the underlying molecular mechanisms for let-7 in regulating innate immunity are still largely unclear.In this study, we investigated the molecular basis for intestinal let-7 in regulating innate immunity in C. elegans. Pseudomonas aeruginosa PA14 infection significantly decreased the let-7::GFP expression, and intestine-or neuron-specific activity of let-7 was required for its function in regulating innate immunity. During the control of innate immune response to P. aeruginosa PA14 infection, SDZ-24, a SKN-1/Nrf dependent protein, was identified as a direct target for intestinal let-7. SDZ-24 is predominantly expressed in the intestine, and P. aeruginosa PA14 infection significantly increased the SDZ-24::GFP expression. Intestinal let-7 could regulate innate immune response to P. aeruginosa PA14 infection by suppressing both the expression and function of SDZ-24. RNAi knockdown of sdz-24 suppressed the resistant property of let-7 mutant to P. aeruginosa PA14 infection, and intestinal overexpression of sdz-24 lacking 3'UTR further inhibited the susceptible property of nematodes overexpressing let-7 in intestine to P. aeruginosa PA 14 infection. In intestine, SDZ-24 could regulate innate immunity by acting upstream of the p38 MAPK signaling pathway. A certain DAF-2-SDZ-24-SKN-1 signaling cascade could also be formed in the intestine for nematodes against the P. aeruginosa PA14 infection, implying that SDZ-24 may serve as an important link between p38 MAPK and insulin signaling pathways in the control of innate immunity.Our results provide the important molecular basis for intestinal let-7 in regulating innate immunity in nematodes. Our results further highlight the crucial role of intestinal miRNAs for animals against the pathogen infection.