UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5
UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5
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DOI：
10.1073/pnas.1322838111
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发表时间：
2014-05-13
影响因子：
11.1
通讯作者：
Kim, You-Me
中科院分区：
文献类型：
--
作者：
Huh, Ji-Won;Shibata, Takuma;Kim, You-Me
Toll样受体(TLRs)的正确转运和定位对于特定的配体识别和有效的信号转导是重要的。TLRs敏感的细菌膜组分在细胞表面表达，并在刺激时向质膜招募信号适配器。相反，核苷酸敏感的TLRs主要存在于细胞内，并以酸性pH依赖的方式从内溶酶体内发出信号。核苷酸敏感的TLRs从内质网到内溶酶体的运输严格依赖于UNC93B1，在携带UNC93B1 H412R突变的3D突变小鼠中，其信号转导完全被取消。相反，在3D小鼠中，通过TLR1、TLR2、TLR4和TLR6传递的信号被认为与细胞表面定位的TLRs无关。出乎意料的是，我们发现细菌鞭毛蛋白的细胞表面受体TLR5也需要UNC93B1来进行质膜定位和信号转导。TLR5与UNC93B1在物理上相互作用，来自3D或UNK93B1缺陷小鼠的细胞不仅在质膜上缺乏TLR5，而且不能分泌细胞因子，也不能在鞭毛刺激下上调共刺激分子，从而证明了UNK93B1在TLR5信号转导中的重要作用。我们的研究表明，unc93B1的作用并不局限于内溶酶体内的TLRs信号转导，并促使我们进一步探讨Ok93B1辅助TLRs差异靶向的机制。
The proper trafficking and localization of Toll-like receptors (TLRs) are important for specific ligand recognition and efficient signal transduction. The TLRs sensing bacterial membrane components are expressed on the cell surface and recruit signaling adaptors to the plasma membrane upon stimulation. On the contrary, the nucleotide-sensing TLRs are mostly found inside cells and signal from the endolysosomes in an acidic pH-dependent manner. Trafficking of the nucleotide-sensing TLRs from the endoplasmic reticulum to the endolysosomes strictly depends on UNC93B1, and their signaling is completely abolished in the 3d mutant mice bearing the H412R mutation of UNC93B1. In contrast, UNC93B1 was considered to have no role for the cell surface-localized TLRs and signaling via TLR1, TLR2, TLR4, and TLR6 is normal in the 3d mice. Unexpectedly, we discovered that TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling. TLR5 physically interacts with UNC93B1, and the cells from the 3d or UNC93B1-deficient mice not only lack TLR5 at the plasma membrane but also fail to secret cytokines and to up-regulate costimulatory molecules upon flagellin stimulation, demonstrating the essential role of UNC93B1 in TLR5 signaling. Our study reveals that the role of UNC93B1 is not limited to the TLRs signaling from the endolysosomes and compels the further probing of the mechanisms underlying the UNC93B1-assisted differential targeting of TLRs.