Tatematsu Megumi, Funami Kenji, Ishii Noriko, Seya Tsukasa, Obuse Chikashi, Matsumoto Misako
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and.
Division of Molecular Life Science, Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan.
J Immunol. 2015 Nov 15;195(10):4933-42. doi: 10.4049/jimmunol.1501305. Epub 2015 Oct 14.
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.
核酸（NA）传感Toll样受体3、7、8和9的区室化受到严格调控，以指导针对微生物感染的最佳反应并避免识别宿主来源的核酸。不协调93同源物B1（UNC93B1）对于将NA传感Toll样受体从内质网（ER）转运到内体/溶酶体是必不可少的。UNC93B1控制Toll样受体加载到COPII囊泡中以从内质网排出，并在稳态下与Toll样受体一起运输。配体诱导的转运也发生在NA传感Toll样受体上。然而，Toll样受体从内质网到内体/溶酶体的配体依赖性转运的分子机制仍不清楚。在本研究中，我们证明富含亮氨酸重复序列蛋白（LRRC）59，一种内质网膜蛋白，参与了NA传感Toll样受体从内质网的转运。敲低LRRC59降低了Toll样受体3、8和9介导的，但不是Toll样受体4介导的信号传导。在配体刺激下，LRRC59以不依赖Toll样受体的方式与UNC93B1结合，这需要配体内化诱导的信号。沉默LRRC59会降低内源性Toll样受体3的内体定位，表明LRRC59在感染时促进UNC93B1介导的NA传感Toll样受体从内质网的转运。这些发现有助于我们理解NA传感Toll样受体如何在感染/炎症状态下控制其适当分布。
