A Conserved p38 Mitogen-Activated Protein Kinase Pathway Regulates Drosophila Immunity Gene Expression

ABSTRACT

Accumulating evidence suggests that the insect and mammalian innate immune response is mediated by homologous regulatory components. Proinflammatory cytokines and bacterial lipopolysaccharide stimulate mammalian immunity by activating transcription factors such as NF-κB and AP-1. One of the responses evoked by these stimuli is the initiation of a kinase cascade that leads to the phosphorylation of p38 mitogen-activated protein (MAP) kinase on Thr and Tyr within the motif Thr-Gly-Tyr, which is located within subdomain VIII. We have investigated the possible involvement of the p38 MAP kinase pathway in the Drosophila immune response. Two genes that are highly homologous to the mammalian p38 MAP kinase were molecularly cloned and characterized. Furthermore, genes that encode two novelDrosophila MAP kinase kinases, D-MKK3 and D-MKK4, were identified. D-MKK3 is an efficient activator of bothDrosophila p38 MAP kinases, while D-MKK4 is an activator of D-JNK but not D-p38. These data establish that Drosophilaindeed possesses a conserved p38 MAP kinase signaling pathway. We have examined the role of the D-p38 MAP kinases in the regulation of insect immunity. The results revealed that one of the functions of D-p38 is to attenuate antimicrobial peptide gene expression following exposure to lipopolysaccharide.

ACKNOWLEDGMENTS

We thank Dan Hultmark for providing the Attacin cDNA probe, Ylva Engstrom for the Cecropin cDNA probe, Kirugaval Hemavathy for help with S2 cell culture, and Catherine Tournier for the MKK amplimers.

This publication was made possible by NIH grants GM53269 (to Y.T.I.) and CA65861 (to R.J.D.). Y.T.I. is a recipient of the Scholar Award of the Leukemia Society of America. R.J.D. is an investigator of the Howard Hughes Medical Institute.

ADDENDUM IN PROOF

The sequence of D-p38a was recently reported by S.-J. Han et al. (J. Biol. Chem. 273:369–374).