UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes
UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes
复制标题
DOI：
10.1038/nature06726
复制
发表时间：
2008-03-13
期刊：
影响因子：
64.8
通讯作者：
Ploegh, Hidde L.
中科院分区：
文献类型：
--
作者：
Kim, You-Me;Brinkmann, Melanie M.;Ploegh, Hidde L.
通过Toll样受体(TLRs)传递信号对于先天性和获得性免疫反应的发展至关重要(1-3)。Ok93B1在人和小鼠体内对TLR3、TLR7和TLR9的信号传递都是必不可少的，它在物理上与内质网(ER)中的这些TLRs相互作用(4-6)。在这里，我们证明了多孔膜蛋白UNC93B1的功能是将核苷酸感测受体TLR7和TLR9从内质网运送到内溶酶体。在3D小鼠的树突状细胞中，表达不能与TLR结合的Ok93B1错义突变体(H412R)，TLR7和TLR9都不退出ER。此外，野生型uc93B1的表达纠正了3D树突状细胞中核苷酸感测TLRs的运输和信号缺陷。然而，在TLRs的配体识别和信号启动过程中，unc93B1是必不可少的。据我们所知，Ok93B1是第一个被鉴定为专门参与核苷酸感应TLR运输的分子。通过抑制Ok93B1和TLRs之间的相互作用，应该可以实现对核苷酸敏感TLRs的特定调控，而不会影响通过细胞表面处理的TLRs的信号转导。
Signalling by means of toll- like receptors ( TLRs) is essential for the development of innate and adaptive immune responses(1-3). UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum ( ER)(4-6). Here we show that the function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide- sensing receptors TLR7 and TLR9 from the ER to endolysosomes. In dendritic cells of 3d mice, which express an UNC93B1 missense mutant ( H412R) incapable of TLR binding, neither TLR7 nor TLR9 exits the ER. Furthermore, the trafficking and signalling defects of the nucleotide- sensing TLRs in 3d dendritic cells are corrected by expression of wild- type UNC93B1. However, UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs. To our knowledge, UNC93B1 is the first protein to be identified as a molecule specifically involved in trafficking of nucleotide- sensing TLRs. By inhibiting the interaction between UNC93B1 and TLRs it should be possible to achieve specific regulation of the nucleotide- sensing TLRs without compromising signalling via the cell- surface- disposed TLRs.