The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.
The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.
复制标题
作者：
哺乳动物 Toll 样受体 (TLR) 3、7、8 和 9 通过识别微生物核酸启动针对感染的免疫反应；然而，由于对自身核酸的不适当识别，这些反应是以潜在的自身免疫为代价的。 TLR9 和 TLR7 在细胞内区室的定位似乎在促进对病毒核酸的反应同时保持对自身核酸的耐受性方面发挥了作用，但调节这些受体的运输和定位的细胞生物学仍然知之甚少。在这里，我们定义了 TLR9 和 TLR7 退出内质网 (ER) 并运输至内溶酶体的路线。令人惊讶的是，TLR9 和 TLR7 的胞外域在内溶酶体中被切割，因此在识别配体的区室中检测不到全长蛋白质。值得注意的是，尽管 TLR9 的全长形式和切割形式都能够结合配体，但只有加工形式在激活后才能招募 MyD88，这表明这种截短的受体（而不是全长形式）具有功能。此外，阻止受体蛋白水解的条件，包括强制 TLR9 表面定位，会使受体失去功能。我们提出，胞外域裂解代表了一种将受体激活限制在内溶酶体区室并防止 TLR 对自身核酸做出反应的策略。
Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids; however, these responses come at the cost of potential autoimmunity due to inappropriate recognition of self nucleic acid. The localization of TLR9 and TLR7 to intracellular compartments appears to play a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acid, yet the cell biology regulating the trafficking and localization of these receptors remains poorly understood. Here, we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum (ER) and traffic to endolysosomes. Surprisingly, the ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Remarkably, though both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 upon activation, arguing that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acid.
影响因子：
64.5
作者：
通讯作者：
--