title: ADP-Ribosylation Factor 3 Mediates Cytidine-Phosphate-Guanosine Oligodeoxynucleotide-Induced Responses by Regulating Toll-Like Receptor 9 Trafficking.
abstract: Toll-like receptor 9 (TLR9) trafficking from the endoplasmic reticulum (ER) into endolysosomes is critical for eliciting cytidine-phosphate-guanosine (CpG) DNA-mediated immune responses. ADP-ribosylation factor 3 (ARF3) is a member of the Ras superfamily, which is crucial for a wide variety of cellular events including protein trafficking. In this study, we found that the inhibition of ARF3 by dominant mutants and siRNA impaired CpG oligodeoxynucleotide (ODN)-mediated responses whereas cells expressing the constitutively active ARF3 mutant enhanced CpG ODN-induced NF-x03BA;B activation and cytokine production. Further experiments with MyD88-overexpressing fibroblast cells transfected with a dominant-negative mutant and a constitutively active mutant of ARF3 demonstrated that ARF3 regulated CpG ODN-mediated signaling upstream of MyD88. Additional studies have shown that ARF3 inhibition impairs TLR9 trafficking from the ER into endolysosomes, thereby inhibiting the functional cleavage of TLR9, although it has no significant effect on CpG ODN uptake. Furthermore, activated ARF3 is associated with Unc93B1 and TLR9, suggesting that ARF3 conducts TLR9 trafficking by forming the TLR9-Unc93B1-ARF3 complex. Overall, our findings demonstrate that a novel ARF3 axis pathway mediates CpG ODN-induced responses by regulating TLR9 trafficking.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, ROC.
authors.forename: Jing-Yiing
authors.initials: JY
authors.lastname: Wu
authors.forename: Cheng-Chin
authors.initials: CC
authors.lastname: Kuo
mesh_terms: D020727:ADP-Ribosylation Factors / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D006801:Humans; D026901:Membrane Transport Proteins / Q000276:immunology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: C408982:CPG-oligonucleotide; C507779:MYD88 protein, human; D026901:Membrane Transport Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C454130:UNC93B1 protein, human; C512254:UNC93B1 protein, mouse; C116687:ARF3 protein, human; D020727:ADP-Ribosylation Factors; C541432:Arf3 protein, mouse