Neuronal GPCR Controls Innate Immunity by Regulating Noncanonical Unfolded Protein Response Genes

Sun, Jesse; Singh, Varsha; Kajino‐Sakamoto, Rie; Aballay, Alejandro

doi:10.1126/science.1203411

Cited by 226 publications

(253 citation statements)

References 18 publications

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“…S2A). By contrast, the noncanonical unfolding protein response (ncUPR), an important defense mechanism against bacterial pathogens (20) and represented by the pqn/abu genes, was not significantly induced ( Fig. S2B), suggesting that B. pseudomallei infection did not elicit the ncUPR response.…”

Section: Resultsmentioning

confidence: 78%

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Lee

Wong

Chin

et al. 2013

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

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Burkholderia pseudomallei is a Gram-negative soil bacterium that infects both humans and animals. Although cell culture studies have revealed significant insights into factors contributing to virulence and host defense, the interactions between this pathogen and its intact host remain to be elucidated. To gain insights into the host defense responses to B. pseudomallei infection within an intact host, we analyzed the genome-wide transcriptome of infected Caenorhabditis elegans and identified ∼6% of the nematode genes that were significantly altered over a 12-h course of infection. An unexpected feature of the transcriptional response to B. pseudomallei was a progressive increase in the proportion of down-regulated genes, of which ELT-2 transcriptional targets were significantly enriched. ELT-2 is an intestinal GATA transcription factor with a conserved role in immune responses. We demonstrate that B. pseudomallei down-regulation of ELT-2 targets is associated with degradation of ELT-2 protein by the host ubiquitin-proteasome system. Degradation of ELT-2 requires the B. pseudomallei type III secretion system. Together, our studies using an intact host provide evidence for pathogen-mediated host immune suppression through the destruction of a host transcription factor.innate immunity | ubiquitin-proteosomal system

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Section: Resultsmentioning

confidence: 78%

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Lee

Wong

Chin

et al. 2013

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

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“…immune systems in insects will likely promote a better understanding of the neural circuits involved in the regulation of immunity in animals (43,46), which appears to be an ancient homeostatic mechanism present also in distant evolutionary lineages such as nematodes (47,48).…”

Section: Resultsmentioning

confidence: 99%

Neonicotinoid clothianidin adversely affects insect immunity and promotes replication of a viral pathogen in honey bees

Prisco

Cavaliere

Annoscia

et al. 2013

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

546

423

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Large-scale losses of honey bee colonies represent a poorly understood problem of global importance. Both biotic and abiotic factors are involved in this phenomenon that is often associated with high loads of parasites and pathogens. A stronger impact of pathogens in honey bees exposed to neonicotinoid insecticides has been reported, but the causal link between insecticide exposure and the possible immune alteration of honey bees remains elusive. Here, we demonstrate that the neonicotinoid insecticide clothianidin negatively modulates NF-κB immune signaling in insects and adversely affects honey bee antiviral defenses controlled by this transcription factor. We have identified in insects a negative modulator of NF-κB activation, which is a leucine-rich repeat protein. Exposure to clothianidin, by enhancing the transcription of the gene encoding this inhibitor, reduces immune defenses and promotes the replication of the deformed wing virus in honey bees bearing covert infections. This honey bee immunosuppression is similarly induced by a different neonicotinoid, imidacloprid, but not by the organophosphate chlorpyriphos, which does not affect NF-κB signaling. The occurrence at sublethal doses of this insecticide-induced viral proliferation suggests that the studied neonicotinoids might have a negative effect at the field level. Our experiments uncover a further level of regulation of the immune response in insects and set the stage for studies on neural modulation of immunity in animals. Furthermore, this study has implications for the conservation of bees, as it will contribute to the definition of more appropriate guidelines for testing chronic or sublethal effects of pesticides used in agriculture.Apis mellifera | DWV | NLR (CLR) | neuroimmunity | toxicology

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“…For example, in the nematode Caenorhabditis elegans , the activity of the AFD neurons is required for the induction of heat‐shock genes in multiple non‐neuronal tissues, demonstrating that a stress response critical in promoting protein homeostasis (proteostasis) is under cell nonautonomous neuronal control (Prahlad et al ., 2008). Moreover, the unfolded protein response of the endoplasmic reticulum (UPR ER ) and the mitochondria (UPR mito ) is also influenced by neuronal function (Durieux et al ., 2011; Sun et al ., 2011; Singh & Aballay, 2012; Taylor & Dillin, 2013). …”

Section: Introductionmentioning

confidence: 99%

Chemical activation of a food deprivation signal extends lifespan

Lucanic

Garrett

et al. 2016

Aging Cell

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SummaryModel organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug‐like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.

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Neuronal GPCR Controls Innate Immunity by Regulating Noncanonical Unfolded Protein Response Genes

Cited by 226 publications

References 18 publications

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Neonicotinoid clothianidin adversely affects insect immunity and promotes replication of a viral pathogen in honey bees

Chemical activation of a food deprivation signal extends lifespan

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