Article | Published:

Activation of a G protein–coupled receptor by its endogenous ligand triggers the innate immune response of Caenorhabditis elegans

Nature Immunology volume 15, pages 833838 (2014) | Download Citation

Abstract

Immune defenses are triggered by microbe-associated molecular patterns or as a result of damage to host cells. The elicitors of immune responses in the nematode Caenorhabditis elegans are unclear. Using a genome-wide RNA-mediated interference (RNAi) screen, we identified the G protein–coupled receptor (GPCR) DCAR-1 as being required for the response to fungal infection and wounding. DCAR-1 acted in the epidermis to regulate the expression of antimicrobial peptides via a conserved p38 mitogen-activated protein kinase pathway. Through targeted metabolomics analysis we identified the tyrosine derivative 4-hydroxyphenyllactic acid (HPLA) as an endogenous ligand. Our findings reveal DCAR-1 and its cognate ligand HPLA to be triggers of the epidermal innate immune response in C. elegans and highlight the ancient role of GPCRs in host defense.

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Acknowledgements

We thank A. Chisholm (University of California, San Diego) for vector pCZGY1434; S. Mitani (Tokyo Women's Medical University School of Medicine) for strain tir-1(tm3036); Y. Goshima (Yokohama City University) for strains dcar-1(nj66) and dcar-1(tm2484), dcar-1 cDNA, and plasmids sra-6pdcar-1Venus and sra-6pdcar-1; C. Bargmann, A. Chisholm, C. Couillault, P. Golstein and E. Vivier for critical reading of the manuscript; M. Metwaly, F. Montañana-Sanchis, S. Omi, J. Soulé and the staff at WormBase and ModulBio for technical support; and C. Melon for advice. Nematode strains pmk-1(km25) and gpa-12(pk322) were provided by the Caenorhabditis Genetics Center, which is funded by the Office of Research Infrastructure Programs of the US National Institutes of Health (P40 OD010440); dcar1(tm2484) was provided by the National Bioresource Project coordinated by S. Mitani. Supported by INSERM, CNRS, the PACA Regional Council, the Agence Nationale de Recherche (MIME-2007, ANR-12-BSV3-0001-01, ANR-11-LABX-0054 (Investissements d'Avenir–Labex INFORM) and ANR-11-IDEX-0001-02 (Investissements d'Avenir–A*MIDEX)), the US National Institutes of Health (GM088290 to F.C.S.) and the Fondation Association pour la Recherche sur le Cancer (B.S.).

Author information

Author notes

    • Barbara Squiban
    •  & C Léopold Kurz

    Present addresses: Section of Hematology/Oncology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA (B.S.), and Institut de Biologie du Développement de Marseille-Luminy, CNRS, UMR6216, Case 907, Marseille, France (C.L.K.).

Affiliations

  1. Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université, Case 906, Marseille, France.

    • Olivier Zugasti
    • , Barbara Squiban
    • , Jérôme Belougne
    • , C Léopold Kurz
    • , Nathalie Pujol
    •  & Jonathan J Ewbank
  2. INSERM, U1104, 13288 Marseille, France.

    • Olivier Zugasti
    • , Barbara Squiban
    • , Jérôme Belougne
    • , C Léopold Kurz
    • , Nathalie Pujol
    •  & Jonathan J Ewbank
  3. CNRS, UMR7280, Marseille, France.

    • Olivier Zugasti
    • , Barbara Squiban
    • , Jérôme Belougne
    • , C Léopold Kurz
    • , Nathalie Pujol
    •  & Jonathan J Ewbank
  4. Department of Chemistry and Chemical Biology, Boyce Thompson Institute, Cornell University, Ithaca, New York, USA.

    • Neelanjan Bose
    •  & Frank C Schroeder

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Contributions

O.Z. designed and did the RNAi screen and most other experiments, analyzed and interpreted the data and helped write the manuscript; B.S., J.B. and C.L.K. did the RNAi screen, analyzed and interpreted the data and reviewed the manuscript; N.B and F.C.S. designed and did the mass spectrometry analyses, analyzed and interpreted data and helped write the manuscript; N.P. designed experiments, analyzed and interpreted data and helped write the manuscript; and J.J.E. conceived of and supervised the project, designed experiments, analyzed and interpreted the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Olivier Zugasti or Jonathan J Ewbank.

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DOI

https://doi.org/10.1038/ni.2957

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