Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to Caenorhabditis elegans

Autor: Robert H. Dowen, Hilary K. Cheesman, Jose Thekkiniath, Annie L. Conery, Read Pukkila-Worley, Rhonda L. Feinbaum
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
MAPK/ERK pathway
C. elegans genetics
MAP Kinase Signaling System
Cellular homeostasis
Gene Expression
Protein Serine-Threonine Kinases
genetics of immunity
QH426-470
p38 Mitogen-Activated Protein Kinases
03 medical and health sciences
0302 clinical medicine
Immune system
RNA interference
Genetics
Animals
host-pathogen interactions
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Molecular Biology
innate immunity
Genetics (clinical)
Alleles
Disease Resistance
Innate immune system
biology
MAP kinase kinase kinase
immune regulation
Genetic Variation
biochemical phenomena
metabolism
and nutrition
biology.organism_classification
Immunity
Innate
3. Good health
Cell biology
Enzyme Activation
030104 developmental biology
Phenotype
Mutation
RNA Interference
030217 neurology & neurosurgery
Genetic screen
Zdroj: G3: Genes, Genomes, Genetics, Vol 6, Iss 3, Pp 541-549 (2016)
G3: Genes|Genomes|Genetics
ISSN: 2160-1836
DOI: 10.1534/g3.115.025650
Popis: Inappropriate activation of innate immune responses in intestinal epithelial cells underlies the pathophysiology of inflammatory disorders of the intestine. Here we examine the physiological effects of immune hyperactivation in the intestine of the nematode Caenorhabditis elegans. We previously identified an immunostimulatory xenobiotic that protects C. elegans from bacterial infection by inducing immune effector expression via the conserved p38 MAP kinase pathway, but was toxic to nematodes developing in the absence of pathogen. To investigate a possible connection between the toxicity and immunostimulatory properties of this xenobiotic, we conducted a forward genetic screen for C. elegans mutants that are resistant to the deleterious effects of the compound, and identified five toxicity suppressors. These strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1, and pmk-1), demonstrating that hyperstimulation of the p38 MAPK pathway is toxic to animals. To explore mechanisms of immune pathway regulation in C. elegans, we conducted another genetic screen for dominant activators of the p38 MAPK pathway, and identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1. The nsy-1(gf) allele caused hyperinduction of p38 MAPK PMK-1-dependent immune effectors, had greater levels of phosphorylated p38 MAPK, and was more resistant to killing by the bacterial pathogen Pseudomonas aeruginosa compared to wild-type controls. In addition, the nsy-1(gf) mutation was toxic to developing animals. Together, these data suggest that the activity of the MAPKKK NSY-1 is tightly regulated as part of a physiological mechanism to control p38 MAPK-mediated innate immune hyperactivation, and ensure cellular homeostasis in C. elegans.
Databáze: OpenAIRE
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