Neuronal GPCR OCTR-1 regulates innate immunity by controlling protein synthesis in Caenorhabditis elegans

Abstract

Upon pathogen infection, microbial killing pathways and cellular stress pathways are rapidly activated by the host innate immune system. These pathways must be tightly regulated because insufficient or excessive immune responses have deleterious consequences. Increasing evidence indicates that the nervous system regulates the immune system to confer coordinated protection to the host. However, the precise mechanisms of neural-immune communication remain unclear. Previously we have demonstrated that OCTR-1, a neuronal G protein-coupled receptor, functions in the sensory neurons ASH and ASI to suppress innate immune responses in non-neural tissues against Pseudomonas aeruginosa in Caenorhabditis elegans. In the current study, by using a mass spectrometry-based quantitative proteomics approach, we discovered that OCTR-1 regulates innate immunity by suppressing translation and the unfolded protein response (UPR) pathways at the protein level. Functional assays revealed that OCTR-1 inhibits specific protein synthesis factors such as ribosomal protein RPS-1 and translation initiation factor EIF-3.J to reduce infection-triggered protein synthesis and UPR. Translational inhibition by chemicals abolishes the OCTR-1-controlled innate immune responses, indicating that activation of the OCTR-1 pathway is dependent on translation upregulation such as that induced by pathogen infection. Because OCTR-1 downregulates protein translation activities, the OCTR-1 pathway could function to suppress excessive responses to infection or to restore protein homeostasis after infection.

Octopaminergic Signaling Mediates Neural Regulation of Innate Immunity in Caenorhabditis elegans

“…Pathogen infection induces secretion of neuropeptides INS-7 and DBL-1 from the nervous system that regulates the expression of immune genes in nonneural tissues ( 19 , 20 , 22 ). We demonstrated that OCTR-1, a putative GPCR for catecholamine expressed in the cilia of neurons located in sensory openings ( 23 ), functions in ASH and ASI sensory neurons to suppress innate immune responses in intestine and pharynx in a cell-non-autonomous manner ( 12 – 14 ). Aballay and colleagues ( 24 ) further pinpointed the finding that ASH neurons control innate immunity whereas ASI neurons promote pathogen avoidance behavior.…”

“…Aballay and colleagues ( 24 ) further pinpointed the finding that ASH neurons control innate immunity whereas ASI neurons promote pathogen avoidance behavior. The OCTR-1-dependent immune regulation is achieved by downregulating gene expression of the PMK-1/p38 MAPK immune pathway and the unfolded protein response (UPR) pathways ( 12 – 14 ). It is not clear what ligand(s) activates OCTR-1 in immune regulation or how the OCTR-1 pathway operates.…”

G Protein-Coupled Receptors Mediate Neural Regulation of Innate Immune Responses in Caenorhabditis elegans

“…A wealth of mammalian studies indicate that the nervous system plays a critical role in the regulation of immune responses [ 23 , 24 ] . Recent studies by us [ 10 , 25 , 26 ] and others [ 9 , 11 – 14 ] have revealed that neural control of innate immunity in mammals has a homologous occurrence in C. elegans , one of the simplest organisms with a nervous system. This indicates that the regulatory mechanism dates back to the origins of the nervous system [ 27 ] .…”

“…Moreover, upon infection with microorganisms, including many human pathogens, C. elegans can mount innate immune responses by activating signaling pathways that are conserved in humans [ 33 – 35 ] . Applying the C. elegans model system to study neural-immune signaling has greatly facilitated our understanding of neural-immune regulatory circuits [ 9 – 14 , 25 , 26 ] .…”

“…Importantly, XBP-1 is not under OCTR-1 control during development, only at the adult stage, indicating the nervous system temporally controls the UPR pathway to maintain endoplasmic reticulum (ER) homeostasis during development and immune activation [ 25 ] . Recently we revealed that OCTR-1 regulates innate immunity at both the transcript and protein levels, and inhibits specific proteins synthesis factors such as ribosomal protein RPS-1 and translation initiation factor EIF-3.J to reduce infection-triggered protein synthesis and UPR [ 26 ] .…”