Caenorhabditis elegansmicroRNAs of thelet-7family act in innate immune response circuits and confer robust developmental timing against pathogen stress

Animals maintain their developmental robustness against natural stresses through numerous regulatory mechanisms, including the posttranscriptional regulation of gene expression by microRNAs (miRNAs).Caenorhabditis elegansmiRNAs of thelet-7family (let-7-Fam) function semiredundantly to confer robust stage specificity of cell fates in the hypodermal seam cell lineages. Here, we show reciprocal regulatory interactions betweenlet-7-FammiRNAs and the innate immune response pathway inC. elegans. Upon infection ofC. eleganslarvae with the opportunistic human pathogenPseudomonas aeruginosa, the developmental timing defects of certainlet-7-FammiRNA mutants are enhanced. This enhancement is mediated by the p38 MAPK innate immune pathway acting in opposition tolet-7-FammiRNA activity, possibly via the downstream Activating Transcription Factor-7 (ATF-7). Furthermore,let-7-FammiRNAs appear to exert negative regulation on the worm’s resistance toP. aeruginosainfection. Our results show that the inhibition of pathogen resistance bylet-7involves downstream heterochronic genes and the p38 MAPK pathway. These findings suggest thatlet-7-FammiRNAs are integrated into innate immunity gene regulatory networks, such that this family of miRNAs modulates immune responses while also ensuring robust timing of developmental events under pathogen stress.