Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9093, USA.
J Biol Chem. 2011 Feb 4;286(5):3307-14. doi: 10.1074/jbc.M110.171025. Epub 2010 Nov 19.
Toll-like receptor (TLR) activation relies on biochemical recognition of microbial molecules and localization of the TLR within specific cellular compartments. Cell surface TLRs largely recognize bacterial membrane components, and intracellular TLRs are exclusively involved in sensing nucleic acids. Here we show that TLR11, an innate sensor for the Toxoplasma protein profilin, is an intracellular receptor that resides in the endoplasmic reticulum. The 12 membrane-spanning endoplasmic reticulum-resident protein UNC93B1 interacts directly with TLR11 and regulates the activation of dendritic cells in response to Toxoplasma gondii profilin and parasitic infection in vivo. A deficiency in functional UNC93B1 protein abolished TLR11-dependent IL-12 secretion by dendritic cells, attenuated Th1 responses against T. gondii, and dramatically enhanced susceptibility to the parasite. Our results reveal that the association with UNC93B1 and the intracellular localization of TLRs are not unique features of nucleic acid-sensing TLRs but is also essential for TLR11-dependent recognition of T. gondii profilin and for host protection against this parasite.
Toll 样受体 (TLR) 的激活依赖于对微生物分子的生化识别和 TLR 在特定细胞区室中的定位。细胞表面 TLR 主要识别细菌膜成分，而细胞内 TLR 专门参与检测核酸。在这里，我们发现 TLR11 是一种对弓形虫蛋白原肌球蛋白的先天传感器，是一种位于内质网中的细胞内受体。12 个跨膜内质网驻留蛋白 UNC93B1 与 TLR11 直接相互作用，并调节树突状细胞对弓形虫原肌球蛋白和体内寄生虫感染的反应中的激活。功能丧失的 UNC93B1 蛋白缺陷会消除 TLR11 依赖性树突状细胞分泌的 IL-12，减弱针对弓形虫的 Th1 反应，并显著增加对寄生虫的易感性。我们的研究结果表明，与 UNC93B1 的关联和 TLR 的细胞内定位不是核酸感应 TLR 的独特特征，对于 TLR11 依赖的弓形虫原肌球蛋白识别和宿主对这种寄生虫的保护也是必不可少的。
