A conserved p38 mitogen-activated protein kinase pathway regulates Drosophila immunity gene expression.
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-kappaB 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 novel Drosophila MAP kinase kinases, D-MKK3 and D-MKK4, were identified. D-MKK3 is an efficient activator of both Drosophila p38 MAP kinases, while D-MKK4 is an activator of D-JNK but not D-p38. These data establish that Drosophila indeed 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.
Han
Z S
ZS
Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, Worcester, Massachusetts 01605, USA.
Enslen
H
H
Hu
X
X
Meng
X
X
Wu
I H
IH
Barrett
T
T
Davis
R J
RJ
Ip
Y T
YT
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D000900:Anti-Bacterial Agents / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004330:Drosophila / Q000235:genetics* / Q000276:immunology*; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D007109:Immunity / Q000235:genetics*; D019476:Insect Proteins / Q000096:biosynthesis / Q000235:genetics; D048371:MAP Kinase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; C488990:AttA protein, Drosophila; C488991:AttB protein, Drosophila; C488989:AttC protein, Drosophila; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019476:Insect Proteins; D011725:Pyridines; C039711:attacin antibacterial protein, insect; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580