It is now clear that pathogens trigger conserved regulatory pathways in C. elegans. These lead to the production of antimicrobial peptides (AMP) and proteins in the intestine and epidermis, under the control of the
p38 MAPK, PMK-1. The protein kinase C delta TPA-1 is required to activate PMK-1 in both tissues, thus defining a core signalling cascade, also involving TIR-1, NSY-1 and SEK-1 {Liberati, 2004; Pujol, 2008}. Outside this core cassette, there is divergence, as for example, the kinase DKF-2, required in the intestine, is not required in the epidermis {Ziegler et al, in press; Ren et al, in press}. In the epidermis, sterile injury also provokes the expression of nlp-family AMP genes. Several mutants with epidermal defects show a high constitutive level of AMP gene expression too. This might serve to prevent any opportunistic infection of the injured epidermis {Pujol et al, 2008b}. In a
dapk-1 (death associated protein kinase) mutant, however, this constitutive expression is not a consequence of the epidermal defects, as a suppressor of the morphological defects,
sydn-1, does not abrogate the high level of AMP expression. Conversely,
pmk-1 abolishes AMP gene expression but has no effect on the morphological phenotype of
dapk-1 mutants. This suggests that
dapk-1 functions as a negative regulator of the epidermal response to damage {Tong et al, 2009}. As GPA-12, a G-alpha protein is required for the regulation of
nlp-29 in the epidermis, one or more GPCRs are likely to contribute to the innate immune response {Ziegler et al, in press}. But just as different signalling components are used in different tissues, so too is there divergence within the epidermis regarding the genes involved in the response to fungal infection and wounding. For example, the Tribbles like kinase NIPI-3 is only require for fungal infection and is therefore of particular interest. We have found that
nipi-3 acts cell autonomously in the epidermis {Pujol, 2008b}, downstream of
dapk-1. We conducted a Y2H screen and identified CEPB-1 as an interactor of NIPI-3. Although alone,
cepb-1 loss of function mutants appear normal,
cepb-1 suppresses the
nipi-3 phenotype, such that a
cepb-1 nipi-3 double mutant is able to respond to infection. CEBP-1 is a homologue of NF-IL6, which functionally interacts with Tribbles 1 in vertebrates {Yamamoto et al, 2007}, further strengthening the notion of deep conservation of innate immune signalling. We are currently studying whether CEBP-1 acts as a repressor of the whole
p38 pathway or is specific to NIPI-3, and whether the physical interaction reflects a translocation of NIPI-3 into the nucleus. Thanks to A. Chisholm, and C. Rubin for sharing unpublished results.