Nucleic acid cellular uptake into endosomes is critical in eliciting nucleotide-sensing toll-like receptors (TLRs) innate immune responses. ADP-ribosylation factor 6 (ARF6) is a member of the Ras superfamily, which is critical to a wide variety of cellular events including endocytosis. Our previous report indicated that ARF6 plays a critical role in CpG ODN/TLR9-mediated responses. Here, we further explored that the basal level of active ARF6 is nonspecifically responsible for initiation of ODNs uptake, which is relatively CpG motif independent. While the initiation of CpG ODN uptake but not GpC ODN uptake can promote TLR9 responses thereby enhancing ARF6 activation which may lead to further nonspecifically increase of cellular uptake of stimulatory CpG ODN as well as nonstimulatory GpC ODN. Because nucleotide-sensing TLR9 plays a role in contributing to immune diseases, selective activation or inhibition of ARF6 might be useful in certain immunological or therapeutic applications.
Keywords: ADP-ribosylation factor 6; CpG oligodeoxynucleotides; Innate immunity; ODN uptake; Toll-like receptor 9 signaling.