Date Published: October 17, 2018
Publisher: Public Library of Science
Author(s): Danfeng Dong, Haisheng Zhou, Soon-Young Na, Rasma Niedra, Yibing Peng, Huajun Wang, Brian Seed, Guo Ling Zhou, Kui Li.
Higher vertebrates have evolved innate and adaptive immune systems to defend against foreign substances and pathogens. Sophisticated regulatory circuits are needed to avoid inappropriate immune responses and inflammation. GPR108 is a seven-transmembrane family protein that activates NF-κB strongly when overexpressed. Surprisingly, its action in a physiological context is that of an antagonist of Toll-like receptor (TLR)-mediated signaling. Cells from Gpr108-null mice exhibit enhanced cytokine secretion and NF-κB and IRF3 signaling, whereas Gpr108-null macrophages reconstituted with GPR108 exhibit blunted signaling. Co-expression of TLRs and GPR108 reduces NF-κB and IFNβ promoter activation compared to expression of either TLRs or GPR108 alone. Upon TLR stimulation GPR108 abundance increases and the protein engages TLRs and their partners to reduce MyD88 expression and interfere with its binding to TLR4 through blocking MyD88 ubiquitination. In turn GPR108 is antagonized by TIRAP, an adaptor protein for TLR and MyD88. The interrelationships between GPR108 and innate immune signaling components are multifactorial and point to a membrane-associated signaling structure of significant complexity.
A human GPR108 cDNA was initially identified among cDNAs enriched for expression in lung. It was found by sequence analysis to fall in the G-protein coupled receptor superfamily and was initially named lung seven transmembrane receptor 2 (LUSTR2). The encoded protein is predicted to bear an amino-terminal hydrophobic signal peptide sequence, a long extracellular domain, and a carboxy-terminal segment containing seven transmembrane domains. The sequence is highly conserved and phylogenetic counterparts can be found throughout the plant and animal kingdoms, in mammals, birds, insects, fish, arthropods, dipterans, nematodes, cress, rice and yeast. The closest ortholog in mammals, Gpr107, shares 49% identity by amino acid sequence with Gpr108 in mice.
Although Gpr108 bears structural similarity to G-protein coupled receptors, to date no study has demonstrated a functional role for the protein. The related gene Gpr107 participates in the regulation of receptor-mediated endocytosis . In this study Gpr108-null mice did not show any gross phenotype whereas Gpr107-null mice exhibited embryonic lethality.