title: The role of UNC93B1 protein in surface localization of TLR3 receptor and in cell priming to nucleic acid agonists.
abstract: Translocation of nucleic acid-sensing (NAS) Toll-like receptors (TLRs) to endosomes is essential for response to microbial nucleic acids as well as for prevention of the autoimmune response. The accessory protein UNC93B1 is indispensable for activation of NAS TLRs because it regulates their response through trafficking to endosomes. We observed that poly(I:C) up-regulates transcription of UNC93B1 and promotes trafficking of TLR3 to the plasma membrane in human epithelial cell line. Up-regulation of UNC93B1 is triggered through TLR3 activation by poly(I:C). Further studies revealed that expression of UNC93B1 promotes trafficking of differentially glycosylated TLR3, but not other NAS TLRs, to the plasma membrane. UNC93B1 promoter region contains binding sites for poly(I:C)- and type I interferon-inducible regulatory elements. UNC93B1 also increases the protein lifetime of TLR3 and TLR9 and augments signaling of all NAS TLRs. Furthermore, we discovered that poly(I:C) pretreatment primes B-cells to the activation by ssDNA via up-regulation of UNC93B1. Our findings identified TLR3 as the important regulator of UNC93B1 that in turn governs the responsiveness of all NAS TLRs.
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, Slovenia.
authors.forename: Jelka
authors.initials: J
authors.lastname: Pohar
authors.forename: Nina
authors.initials: N
authors.lastname: Pirher
authors.forename: Mojca
authors.initials: M
authors.lastname: Benčina
authors.forename: Mateja
authors.initials: M
authors.lastname: Manček-Keber
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D042783:Endothelial Cells / Q000166:cytology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000502:physiology*; D009696:Nucleic Acids / Q000819:agonists*; D011070:Poly I-C / Q000378:metabolism; D034622:RNA Interference; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D026901:Membrane Transport Proteins; D009696:Nucleic Acids; C495344:TLR3 protein, human; C495371:TLR9 protein, human; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; C454130:UNC93B1 protein, human; D016899:Interferon-beta; D011070:Poly I-C