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UNC93B1蛋白调控TLR的区域化激活
2019-09-24 16:11

美国加州大学伯克利分校的Gregory M. Barton研究组发现UNC93B1的释放加强了部分Toll样受体(TLR)的区域化激活。相关论文2019年9月23日在线发表于《自然》。

研究人员描述了一种防止内吞体以外的位置激活TLR9的新机制。这种控制是通过受体从其运输伴侣UNC93B1的释放来实现的,该释放仅在内吞体中发生,是配体结合和信号转导所必需的。通过UNC93B1中增加对TLR9的亲和力的突变或通过削弱释放的人工系链来阻止TLR9从UNC93B1中释放,会导致信号缺陷。TLR9和TLR3从UNC93B1释放时,TLR7在内吞体中并未从UNC93B1上解离,而是通过不同的机制进行调控。

这项工作定义了一个新的检查点,其加强了TLR9的区域化激活,并为明确调控单个內吞体内TLR的激活提供了一个机制。

研究人员表示,核酸敏感的TLR受到复杂的调节,以促进微生物DNA和RNA的识别,同时限制对自身核酸的识别。无法正确调节这些TLR会导致自身免疫和自身炎症性疾病。人们认为这些受体的细胞内定位对于自我与非自我辨别是至关重要的,但是增强细胞内TLR的区域化激活的分子机制仍然知之甚少。

附:英文原文

Title: Release from UNC93B1 reinforces the compartmentalized activation of select TLRs

Author: Olivia Majer, Bo Liu, Brian J. Woo, Lieselotte S. M. Kreuk, Erik Van Dis, Gregory M. Barton

Issue&Volume: 2019-09-23

Abstract: 

Nucleic acid-sensing Toll-like receptors (TLRs) are subject to complex regulation to facilitate recognition of microbial DNA and RNA while limiting recognition of self-nucleic acids1. Failure to properly regulate these TLRs can lead to autoimmune and autoinflammatory disease2–6. Intracellular localization of these receptors is thought to be critical for self versus non-self discrimination7, yet the molecular mechanisms that reinforce compartmentalized activation of intracellular TLRs remain poorly understood. Here we describe a new mechanism that prevents TLR9 activation from locations other than endosomes. This control is achieved through the regulated release of the receptor from its trafficking chaperone UNC93B1, which occurs only within endosomes and is required for ligand binding and signal transduction. Preventing TLR9 release from UNC93B1, either through mutations in UNC93B1 that increase affinity for TLR9 or through an artificial tether that impairs release, results in defective signalling. While TLR9 and TLR3 release from UNC93B1, TLR7 does not dissociate from UNC93B1 in endosomes and is regulated via distinct mechanisms. This work defines a new checkpoint that reinforces compartmentalized activation of TLR9 and provides a mechanism by which activation of individual endosomal TLRs may be distinctly regulated.

DOI: 10.1038/s41586-019-1611-7

Source:https://www.nature.com/articles/s41586-019-1611-7

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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