ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination.
ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination.
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DOI：
10.1016/j.immuni.2016.07.010
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发表时间：
2016-08-16
期刊：
影响因子：
32.4
通讯作者：
Krämer H
中科院分区：
文献类型：
--
作者：
Akbar MA;Mandraju R;Tracy C;Hu W;Pasare C;Krämer H
Toll 样受体 (TLR) 和其他模式识别受体 (PRR) 感知微生物配体并启动信号传导以诱导炎症反应。尽管炎症反应的质量受到 TLR 内化的影响，但内体成熟在清除受体和终止炎症反应中的作用尚不清楚。在此，我们报告果蝇和哺乳动物 Vps33B 蛋白在微生物识别后吞噬体和内体的成熟中发挥关键作用。 Vps33B 对于清除含有内化 PRR 的内体是必需的，其失败会导致信号传导和炎症介质表达增强。缺乏 Vps33B 对含有非微生物货物的内体运输没有影响。这些发现表明，Vps33B 功能对于确定 PRR 激活后形成的信号内体的命运至关重要。因此，异常内体区室中受体的持续存在所导致的过度炎症反应可能会导致 ARC 综合征的症状，这是一种与 Vps33B 缺失相关的疾病。 VPS33B 基因的功能突变会导致一种称为 ARC 综合征的致命人类疾病。 Pasare 及其同事证明，PRR 的激活会导致炎症内体的形成，而炎症内体需要 Vps33B 才能成熟。 Vps33B 功能的丧失会导致 PRR 及其配体在内体内积聚，从而导致炎症反应加剧。
Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) sense microbial ligands and initiate signaling to induce inflammatory responses. Although the quality of inflammatory responses is influenced by internalization of TLRs, the role of endosomal maturation in clearing receptors and terminating inflammatory responses is not well understood. Here, we report that Drosophila and mammalian Vps33B proteins play critical roles in the maturation of phagosomes and endosomes following microbial recognition. Vps33B was necessary for clearance of endosomes containing internalized PRRs, failure of which resulted in enhanced signaling and expression of inflammatory mediators. Lack of Vps33B had no effect on trafficking of endosomes containing non-microbial cargo. These findings indicate that Vps33B function is critical for determining the fate of signaling endosomes formed following PRR activation. Exaggerated inflammatory responses dictated by persistence of receptors in aberrant endosomal compartments could therefore contribute to symptoms of ARC syndrome, a disease linked to loss of Vps33B. Functional mutations in VPS33B gene lead to a fatal human disease called ARC syndrome. Pasare and colleagues demonstrate that activation of PRRs leads to formation of inflammatory endosomes that require Vps33B for maturation. Loss of Vps33B function causes endosomal accumulation of PRRs and their ligands leading to exaggerated inflammatory responses.