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

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 RNAi screen, we identify the G-protein coupled receptor (GPCR) DCAR-1 as being required for the response to fungal infection and wounding. DCAR-1 acts in the epidermis to regulate the expression of antimicrobial peptides via a conserved p38 mitogen-activated protein kinase pathway. Through targeted metabolomics analysis we identify the tyrosine-derivative 4-hydroxyphenyllactic acid (HPLA) as an endogenous ligand. These findings reveal DCAR-1 and its cognate ligand HPLA to be important triggers of the epidermal innate immune response in C. elegans and highlight the ancient role of GPCRs in host defense.

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

“…38), but we observed that genetic ablation of dcar-1 did not rescue motility defects or neurodegeneration phenotypes caused by mutant TDP-43. These data suggest that other receptor proteins may be responsible for modulating neuronal degeneration in conjunction with TIR-1.…”

“…TIR-1 is an adaptor protein believed to mediate signalling downstream from an otherwise unknown cell surface receptor proteins. Recently, the dihydrocaffeic acid receptor DCAR-1 was identified as a component of the TIR-1 signalling pathway in response to epidermal infection 38 . We wondered whether DCAR-1 also contributed to neurodegeneration from mutant ALS proteins, but found that dcar-1 null mutations failed to suppress mutant TDP-43-mediated paralysis and motor neuron degeneration (Supplementary Fig.…”

Antimicrobial effectors in the nematode Caenorhabditis elegans : an outgroup to the Arthropoda

“…These might thus play more general roles in immunity, as most clearly demonstrated thus far for the nlp and cnc genes and their particular contribution to anti-fungal defence (e.g. [21,44,45]). It is worth noting that none of the considered effector genes show a change in expression after infection with Orsay virus (except downregulation of nlp-28).…”

“…Recognition of bacterial and fungal pathogens is less clear. A G protein-coupled receptor was implicated in the indirect recognition of the fungal pathogen D. coniospora via the perception of a so-called damage-associated molecular pattern (DAMP) [21]. Indirect pathogen detection also seems to be achieved through a cellular surveillance system, which activates pathogen defence responses when central cellular processes are disrupted [17,22].…”

“…The main exception refers to nlp-29, for which an endogenous danger signal triggers gene expression [46] and which is regulated through a complex signalling network (e.g. [21,25,45,46]). Further analysis of the exact regulation of antimicrobial effector genes would be of great value for understanding their role in defence.…”