Host defense in C. elegans requires a conserved TIR-1-NSY-1-SEK-1-
p38 mitogen-activated protein kinase (MAPK) cascade. The TIR-1-NSY-1-SEK-1 module has dual tissue-specific roles in response to pathogen; in the intestine this module regulates the expression of immune effector genes, whereas in the sensory nervous system this module regulates serotonin-dependent aversive behavior. The
p38 MAPK PMK-1 functions downstream of this module to regulate the response to pathogen in the intestine. We performed a forward genetic screen for suppressors of the enhanced susceptibly to pathogen conferred by
pmk-1 loss-of-function and identified an allele of
pmk-2,
qd171. The
pmk-2 gene is paralogous to
pmk-1 and encodes a
p38 MAPK. The
pmk-1 and
pmk-2 genes are clustered together in an operon, although their expression patterns differ. We observe nearly ubiquitous expression of
pmk-1, whereas
pmk-2 is expressed specifically in the nervous system. The
qd171 allele of
pmk-2 contains an insertion/deletion in the 3' UTR that allows for expression of
pmk-2 in the intestine where it can compensate for loss of
pmk-1 function. We found highly conserved microRNA seed match sites for the
mir-58 family of microRNAs in the 3' UTR of
pmk-2 that are absent in the
qd171 mutant. We determined the
mir-58 family of microRNAs acts to inhibit expression of
pmk-2 in the intestine and establishes tissue-specificity of
p38 MAPKs that are co-transcribed. We next isolated a loss-of-function allele of
pmk-2,
qd279, and defined a physiological role for PMK-2 in regulating serotonin-dependent behaviors of host defense. These data demonstrate that the
mir-58 family of microRNAs governs the tissue-specific expression of
p38 MAPKs that act through distinct modes to provide host defense against pathogen.