Biochemistry & Molecular Pharmacology
Program in Molecular Medicine; RNA Therapeutics Institute
Medical Subject Headings
Alleles; Animals; Caenorhabditis elegans; Cell Lineage; Gene Expression Regulation; Gene Regulatory Networks; Genes, Reporter; Immune System; *Immunity, Innate; MicroRNAs; Microscopy, Confocal; Microscopy, Electron, Transmission; Mutation; Phenotype; Pseudomonas Infections; Pseudomonas aeruginosa; Signal Transduction; Treatment Outcome; p38 Mitogen-Activated Protein Kinases
Developmental Biology | Genetics and Genomics | Immunity | Immunopathology | Molecular Genetics
Animals maintain their developmental robustness against natural stresses through numerous regulatory mechanisms, including the posttranscriptional regulation of gene expression by microRNAs (miRNAs). Caenorhabditis elegans miRNAs of the let-7 family (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 between let-7-Fam miRNAs and the innate immune response pathway in C. elegans. Upon infection of C. elegans larvae with the opportunistic human pathogen Pseudomonas aeruginosa, the developmental timing defects of certain let-7-Fam miRNA mutants are enhanced. This enhancement is mediated by the p38 MAPK innate immune pathway acting in opposition to let-7-Fam miRNA activity, possibly via the downstream Activating Transcription Factor-7 (ATF-7). Furthermore, let-7-Fam miRNAs appear to exert negative regulation on the worm's resistance to P. aeruginosa infection. Our results show that the inhibition of pathogen resistance by let-7 involves downstream heterochronic genes and the p38 MAPK pathway. These findings suggest that let-7-Fam miRNAs 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.
Rights and Permissions
Citation: Proc Natl Acad Sci U S A. 2015 May 5;112(18):E2366-75. doi: 10.1073/pnas.1422858112. Epub 2015 Apr 20. Link to article on publisher's site
DOI of Published Version
Pseudomonas aeruginosa, developmental timing, innate immunity, let-7 family microRNAs, p38
Proceedings of the National Academy of Sciences of the United States of America
Ren, Zhiji and Ambros, Victor R., "Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress" (2015). GSBS Student Publications. 1884.