Cryo-EM structures of Toll-like receptors in complex with UNC93B1
Cryo-EM structures of Toll-like receptors in complex with UNC93B1
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DOI：
10.1038/s41594-020-00542-w
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发表时间：
2021-01-11
影响因子：
16.8
通讯作者：
Shimizu, Toshiyuki
中科院分区：
文献类型：
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作者：
Ishida, Hanako;Asami, Jinta;Shimizu, Toshiyuki
核酸敏感Toll样受体（TLR）通过识别外源DNA和RNA在先天免疫中发挥关键作用。这些TLR在内体中的区室化限制了它们被自身衍生的核酸激活，并降低了自身免疫反应的可能性。虽然分子伴侣Unc-93同源物B1，TLR信号转导调节子（UNC 93 B1）对于TLR从内质网到核内体的运输是不可或缺的，但UNC 93 B1介导的TLR调节的机制在很大程度上仍然未知。在这里，我们报告了人和小鼠TLR 3-UNC 93 B1复合物和人TLR 7-UNC 93 B1复合物的两种冷冻电镜结构。UNC 93 B1与主要易化超家族转运蛋白具有结构相似性。两种TLR均通过其跨膜和管腔内膜区域与UNC 93 B1氨基末端六螺旋束相互作用，但TLR 3和TLR 7与UNC 93 B1的复合物在其寡聚化状态方面不同。这里提供的结构信息应该有助于设计对抗自身免疫性疾病的化合物。
Nucleic acid-sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. Here, we report two cryo-EM structures of human and mouse TLR3-UNC93B1 complexes and a human TLR7-UNC93B1 complex. UNC93B1 exhibits structural similarity to the major facilitator superfamily transporters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state. The structural information provided here should aid in designing compounds to combat autoimmune diseases.