A CONSERVED P38 MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY REGULATES DROSOPHILA IMMUNITY GENE-EXPRESSION

Accumulating evidence suggests that the insect and mammalian innate im mune response is mediated by homologous regulatory components. Proinfl ammatory cytokines and bacterial lipopolysaccharide stimulate mammalia n immunity by activating transcription factors such as NF-kappa B and AP-1. One of the responses evoked by these stimuli is the initiation o f a kinase cascade that leads to the phosphorylation of p38 mitogen-ac tivated protein (MAP) kinase on Thr and Tyr within the motif Thr-Gly-T yr, which is located within subdomain VIII. We have investigated the p ossible involvement of the p38 MAP kinase pathway in the Drosophila im mune response. Two genes that are highly homologous to the mammalian p 38 MAP kinase were molecularly cloned and characterized. Furthermore, genes that encode two novel Drosophila MAP kinase kinases, D-MKK3 and D-MKK4, were identified. D-MKK3 is an efficient activator of both Dros ophila p38 MAP kinases, while D-MKK4 is an activator of D-JNK but not D-p38. These data establish that Drosophila indeed possesses a conserv ed p38 MAP kinase signaling pathway. We have examined the role of the D-p38 MAP kinases in the regulation of insect immunity. The results re vealed that one of the functions of D-p38 is to attenuate antimicrobia l peptide gene expression following exposure to lipopolysaccharide.