Abstract
Esophageal cancer-related gene 4 (Ecrg4) encodes a hormone-like peptide that is believed to be involved in a variety of physiological phenomena, including tumour suppression. Recent progress in the study of Ecrg4 has shown that Ecrg4 is a proinflammatory factor and induces the expression of several cytokines and chemokines in macrophages/microglia. However, the detailed molecular mechanisms of Ecrg4 signalling, especially the Ecrg4 receptors, remain poorly understood. Here, using retrovirus-mediated expression cloning, we identified lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) as a membrane protein that binds amino acid residues 71–132 of Ecrg4 (Ecrg4(71–132)). Moreover, in addition to LOX-1, several scavenger receptors, such as Scarf1, Cd36 and Stabilin-1, facilitated the efficient internalisation of Ecrg4(71–132) into cells. A broad competitive inhibitor of scavenger receptors, polyinosinic acid, reduced both the binding of Ecrg4(71–132) and the activation of NF-κB in microglia. This activation was dependent on MyD88, an adaptor protein that recruits signalling proteins to Toll-like receptors (TLRs), with the consequent induction of various immune responses. These data suggest that multiple scavenger receptors recognise Ecrg4(71–132) and transduce its signals, together with TLRs, in microglia.
Highlights
Peptide hormones regulate many biological processes, and in many cases, their biological information is transduced into the target cells through specific receptors
We demonstrated for the first time that Esophageal cancer-related gene 4 (Ecrg4)(71–132) binds to multiple scavenger receptors that activate the innate immune responses24 and maintain homeostasis by clearing modified lipoproteins, pathogens and apoptotic cells23
LOX-1, which binds with ox-LDL, rapidly increased reactive oxygen species levels and activated the NF-κB signalling pathway31,32, while with the outer membrane protein A (OmpA), LOX-1 triggered the innate immune response via a TLR2-dependent pathway33
Summary
Peptide hormones regulate many biological processes, and in many cases, their biological information is transduced into the target cells through specific receptors. Several reports have shown that Ecrg inhibits cell proliferation, accumulating evidence including ours indicates proinflammatory functions for the Ecrg peptides: cerebral ventricular injection of amino acids 71–148 of Ecrg increased plasma adrenocorticotropic hormone and corticosterone in rats. The C-terminal Ecrg peptide containing amino acids 133–148 (Ecrg4(133–148)) activated the NF-κB pathway in macrophages and interacted with the innate immunity receptor complex (Toll-like receptor 4 (TLR4)/CD14/MD2 complex). Ecrg4(71– 132) and Ecrg4(133–148) activated macrophages/microglia and induced the expression of several cytokines and chemokines, which contribute, at least in part, to the antitumour function of Ecrg410. Ecrg4(71– 132) and Ecrg4(133–148) activated macrophages/microglia and induced the expression of several cytokines and chemokines, which contribute, at least in part, to the antitumour function of Ecrg410,11 Together, these findings suggest that Ecrg acts as an inflammatory cytokine that regulates many physiological processes, rather than a traditional tumour suppressor. To unravel the molecular mechanisms of the Ecrg signalling pathways, we searched for Ecrg receptors in this study
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