Antifungal Innate Immunity in C. elegans: PKCδ Links G Protein Signaling and a Conserved p38 MAPK Cascade

Ziegler, Katja; Kurz, C. Léopold; Cypowyj, Sophie; Couillault, Carole; Pophillat, Matthieu; Pujol, Nathalie; Ewbank, Jonathan J.

doi:10.1016/j.chom.2009.03.006

Cited by 108 publications

(147 citation statements)

References 38 publications

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“…An ortholog of the heterotrimeric G protein alpha subunit Gq, egl-30, (Wang and Wadsworth 2002) and its downstream player, egl-8, (Ziegler et al 2009) in C. elegans plays a pivotal role in regulating pharyngeal pumping, egg laying and locomotion (Govorunova et al 2010). Previous reports suggest that mutation in goa-1 has a negative impact on egg laying, locomotion, and other normal behaviors of the worm (Matsuki et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Ultraviolet-A triggers photoaging in model nematode Caenorhabditis elegans in a DAF-16 dependent pathway

Prasanth

Santoshram

Bhaskar

et al. 2016

AGE

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Ultraviolet radiations (UV) are the primary causative agent for skin aging (photoaging) and cancer, especially UV-A. The mode of action and the molecular mechanism behind the damages caused by UV-A is not well studied, in vivo. The current study was employed to investigate the impact of UV-A exposure using the model organism, Caenorhabditis elegans. Analysis of lifespan, healthspan, and other cognitive behaviors were done which was supported by the molecular mechanism.

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Section: Discussionmentioning

confidence: 99%

Ultraviolet-A triggers photoaging in model nematode Caenorhabditis elegans in a DAF-16 dependent pathway

Prasanth

Santoshram

Bhaskar

et al. 2016

AGE

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“…egl-8 also appears to contribute to the response of epidermal tissues to infection by Microbacterium nematophilum (34) and Drechmeria conidispora (35). M. nematophilum adheres to the postanal cuticle and rectum of C. elegans, and the host induces a defense response that involves swelling of the underlying hypodermal tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Upon D. coniospora infection, the host's underlying epidermis responds by up-regulating the expression of antimicrobial genes, including nlp-29. nlp-29 induction requires EGL-8 and the p38 MAPK signaling cascade (35). Given that both reporter GFP and antibody analyses did not detect egl-8 expression in the epidermis (21), it remains to be determined whether the Graphs show survival of wild-type (N2), egl-8(n488) compared with sek-1 (km4), egl-8(n488); sek-1(km4) (A and C) and to daf-16(mu86) and egl-8 (n488); daf-16(mu86) (B and D) after exposure to 3 mM arsenite (A and B) or P. aeruginosa (C and D).…”

Section: Discussionmentioning

confidence: 99%

Systemic and cell intrinsic roles of Gqα signaling in the regulation of innate immunity, oxidative stress, and longevity in Caenorhabditis elegans

Kawli

Wu²,

Tan³

2010

Proc. Natl. Acad. Sci. U.S.A.

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Signal transduction pathways that regulate longevity, immunity, and stress resistance can profoundly affect organismal survival. We show that a signaling module formed by the G protein alpha subunit, Gqα, and one of its downstream signal transducer phospholipase C β (PLCβ) can differentially affect these processes. Loss of Gqα and PLCβ functions result in increased sensitivity to pathogens and oxidative stress but confer life span extension. Gqα and PLCβ modulate life span and immunity noncell autonomously by affecting the activity of insulin/IGF1 signaling (IIS). In addition, Gqα and PLCβ function cell autonomously within the intestine to affect the activity of the p38 MAPK pathway, an important component of Caenorhabditis elegans immune and oxidative stress response. p38 MAPK activity in the intestine is regulated by diacylglycerol levels, a product of PLCβ's hydrolytic activity. We provide genetic evidence that life span is largely determined by IIS, whereas p38 MAPK signaling is the primary regulator of oxidative stress in PLCβ mutants. Pathogen sensitivity of Gqα and PLCβ mutants is a summation of the beneficial effects of decreased IIS through reduced neuronal secretion and the detrimental effects of reduced activity of intestinal p38 MAPK. We propose a model whereby Gqα signaling differentially regulates pathogen sensitivity, oxidative stress, and longevity through cell autonomous and noncell autonomous effects on p38 MAPK and insulin/IGF1 signaling, respectively.insulin/IGF-1 signaling | p38 MAPK signaling | infection | aging A ppropriate responses to endogenous and exogenous threats at the organismal level are achieved by the coordination and integration of both cell-intrinsic and systemic signaling events. The conserved insulin/IGF1 signaling (IIS) pathway regulates life span, stress responses, and immunity. In Caenorhabditis elegans, activation of the insulin/IGF1-like receptor (IGFR) DAF-2 results in phosphorylation and retention of the forkhead transcription factor DAF-16 in the cytoplasm (1). Reduction in IGFR function results in increased life span and oxidative stress resistance in C. elegans (2, 3), Drosophila (4), and mice (5). Oxidative stress response is also regulated by the p38 MAPK cascade, which in C. elegans comprises of a three-tiered kinase cascade leading to phosphorylation by a MAPK kinase homolog SEK-1 and activation of the p38 MAPK homolog PMK-1 (6). Loss of either sek-1 or pmk-1 function results in increased sensitivity to oxidative stress (7). The p38 MAPK pathway affects oxidative stress resistance cell autonomously in part through regulation of the Nrf family transcription factor SKN-1 in the intestine (8, 9).IIS and p38 MAPK signaling contribute to C. elegans immunity. Diminished IIS confers pathogen resistance because of derepression of DAF-16 transcriptional activity and increased immuneeffector gene expression (10, 11), whereas diminished p38 MAPK signaling confers increased pathogen sensitivity (12); these pathways regulate distinct sets of immune-related genes (13-15). Re...

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“…First, the tir-1(ok1052) allele that lacks the N-terminal Heat/Armadillo motif of the protein blocks the enhancement of let-7-Fam miRNA mutant phenotypes (Fig. S2A), even though this motif has been shown to be dispensable for pathogen resistance (43,44). This result suggests that activation of the p38 MAPK pathway is necessary for the regulation of let-7-Fam miRNA activity upon P. aeruginosa infection but that p38 signaling alone without the activity of the Heat/Armadillo motif of TIR-1 is not sufficient.…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

Ren

Ambros

2015

Proc. Natl. Acad. Sci. U.S.A.

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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.let-7 family microRNAs | p38 | Pseudomonas aeruginosa | developmental timing | innate immunity D uring development, animals routinely encounter environmental, physiological, and nutritional challenges that threaten to compromise the robust execution of developmental programs. Therefore, the genetic programming of development includes mechanisms to ensure that developmental events occur flawlessly despite stressful conditions (1, 2). Several studies indicate that microRNAs (miRNAs) are used to maintain the robustness of biological processes under stress conditions (3-10). miRNAs are endogenous, noncoding, small RNAs that posttranscriptionally regulate gene expression primarily through binding to the 3′UTR of target mRNAs, which results in translation inhibition and/or mRNA degradation (11). miRNAs with the same seed sequence (nucleotides 2-7 of the mature miRNA sequence), which are predicated potentially to share the same set of targets (12), are grouped into a family.The miRNA lin-4 and the miRNAs of the let-7 family (let-7-Fam) are central to the regulation of pluripotency and differentiation in many animal systems, including mammals (13-18). Four Caenorhabditis elegans let-7-Fam miRNAs, let-7, mir-48, mir-84, and mir-241, function in concert to repress key heterochronic gene targets, including daf-12, lin-41, and hbl-1, to stagespecifically regulate the timing of the hypodermal seam cell fates (16,(19)(20)(21)(22). In C. elegans, the temporal patterns of cell division and cell fate during larval development are exquisitely invariant, even though larvae develop as free-living inhabitants of a changing environment in soil and decaying plant materials.In the wild, worms...

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Antifungal Innate Immunity in C. elegans: PKCδ Links G Protein Signaling and a Conserved p38 MAPK Cascade

Cited by 108 publications

References 38 publications

Ultraviolet-A triggers photoaging in model nematode Caenorhabditis elegans in a DAF-16 dependent pathway

Ultraviolet-A triggers photoaging in model nematode Caenorhabditis elegans in a DAF-16 dependent pathway

Systemic and cell intrinsic roles of Gqα signaling in the regulation of innate immunity, oxidative stress, and longevity in Caenorhabditis elegans

Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

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