title: TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements.
abstract: Toll-like receptor (TLR) 3 and TLR7 are indispensable for host defense against viral infection by recognizing virus-derived RNAs and are localized to intracellular membranes via an unknown mechanism. We recently reported experiments with chimeric Toll-like receptors that suggested that the subcellular distribution of TLRs may be defined by their transmembrane and/or cytoplasmic domains. Here we demonstrate that the intracellular localization of TLR3 is achieved by a 23-amino acid sequence (Glu(727) to Asp(749)) present in the linker region between the transmembrane domain and Toll-interleukin 1 receptor resistance (TIR) domain. In contrast, the intracellular localization of TLR7 is achieved by its transmembrane domain. These elements also targeted a heterologous type I transmembrane protein CD25 to the intracellular compartment that contained TLR3 and TLR7. Despite their using distinct regulatory elements for intracellular localization, TLR3 was found to co-localize with TLR7. In addition, TLR3 and TLR7 were preferentially localized near phagosomes containing apoptotic cell particles. These findings reveal that TLR3 and TLR7 contain unique targeting sequences, which differentially lead them to the same intracellular compartments and adjacent to phagosomes containing apoptotic cell particles, where these receptors may access their ligands for the induction of immune responses against viral infection.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nishiya
authors.forename: Emi
authors.initials: E
authors.lastname: Kajita
authors.forename: Soichi
authors.initials: S
authors.lastname: Miwa
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Defranco
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D010588:Phagosomes / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7