The
p38 and JNK MAP kinase pathways play central roles in the stress response and immune signaling pathways of evolutionarily diverse species. We have recently established that the NSY-1(MAPKKK)-SEK-1(MAPKK)-PMK-1
(p38 MAPK) pathway plays a crucial role in mediating pathogen resistance in C. elegans (1). Here, we present studies on the possible involvement of additional
p38 and JNK MAP kinase signaling pathway components in the regulation of the C. elegans immune response. The
mek-1(
ks54) null mutant (2) exhibits an enhanced susceptibility to pathogens (Esp) phenotype, though not as strong as that observed for the
sek-1 mutant. Although a recent study suggested that
mek-1(
ks54) functions upstream of the
jnk-1 gene that encodes a JNK MAP kinase homolog in mediating resistance to heavy metals (3), we do not observe an Esp phenotype in the
jnk-1 mutant. Instead, we observe diminished levels of PMK-1 activation in the
mek-1 mutant, and further genetic analysis suggests that both
sek-1 and
mek-1 function upstream of a common MAPK target,
pmk-1. The activation of PMK-1 by SEK-1 and MEK-1 is balanced by negative regulation mediated in part by VHP-1, a dual-specificity MAP kinase phosphatase. RNAi of
vhp-1 suppresses the Esp phenotype of
mek-1. In turn, a slow growth phenotype has been noted with RNAi of
vhp-1 in wild-type worms (4); interestingly, this slow growth is suppressed in both
mek-1 and
sek-1 backgrounds. The mutual genetic suppression of the slow growth and Esp phenotypes of the
vhp-1 and
mek-1 genes, respectively, suggests corresponding negative and positive regulation of a common MAP kinase target, likely PMK-1. Our genetic and biochemical data suggest that MEK-1 and VHP-1, in concert with SEK-1, function to modulate the activity of PMK-1
p38 MAP kinase and suggest that the further genetic dissection of immune signaling in C. elegans may reveal additional regulatory elements of the conserved
p38 MAP kinase signaling cascade. References 1. Kim et al. (2002), Science 297, 623-626. 2. Koga et al. (2000), EMBO J. 19, 5148-5156. 3. Villanueva et al. (2002), EMBO J. 20, 5114-5128. 4. Kamath et al. (2003), Nature 421, 231-237.