title: LRRC59 Regulates Trafficking of Nucleic Acid-Sensing TLRs from the Endoplasmic Reticulum via Association with UNC93B1.
abstract: Compartmentalization of nucleic acid (NA)-sensing TLR3, 7, 8, and 9 is strictly regulated to direct optimal response against microbial infection and evade recognition of host-derived NAs. Uncoordinated 93 homolog B1 (UNC93B1) is indispensable for trafficking of NA-sensing TLRs from the endoplasmic reticulum (ER) to endosomes/lysosomes. UNC93B1 controls loading of the TLRs into COPII vesicles to exit from the ER and traffics with the TLRs in the steady state. Ligand-induced translocation also happens on NA-sensing TLRs. However, the molecular mechanism for ligand-dependent trafficking of TLRs from the ER to endosomes/lysosomes remains unclear. In this study, we demonstrated that leucine-rich repeat containing protein (LRRC) 59, an ER membrane protein, participated in trafficking of NA-sensing TLRs from the ER. Knockdown of LRRC59 reduced TLR3-, 8-, and 9-mediated, but not TLR4-mediated, signaling. Upon ligand stimulation, LRRC59 associated with UNC93B1 in a TLR-independent manner, which required signals induced by ligand internalization. Endosomal localization of endogenous TLR3 was decreased by silencing of LRRC59, suggesting that LRRC59 promotes UNC93B1-mediated translocation of NA-sensing TLRs from the ER upon infection. These findings help us understand how NA-sensing TLRs control their proper distribution in the infection/inflammatory state.
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and.
authors.forename: Megumi
authors.initials: M
authors.lastname: Tatematsu
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.affiliation: Division of Molecular Life Science, Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Obuse
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and matumoto@pop.med.hokudai.ac.jp.
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology*; D011992:Endosomes / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007239:Infections / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology*; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*
chemical_list: C574205:LRRC59 protein, human; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051193:Toll-Like Receptors; C454130:UNC93B1 protein, human