Hypersensitivity of Vps33B mutant flies to non-pathogenic infections is dictated by aberrant activation of p38b MAP kinase.
Hypersensitivity of Vps33B mutant flies to non-pathogenic infections is dictated by aberrant activation of p38b MAP kinase.
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DOI：
10.1111/tra.12756
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Krämer H
中科院分区：
文献类型：
--
作者：
Zhang J;Tracy C;Pasare C;Zeng J;Krämer H
在脊椎动物和果蝇中，关节挛缩-肾功能障碍-胆汁淤积（ARC）综合征相关的Vps33B蛋白的缺失导致先天免疫系统受体激活时的炎症反应被夸大。然而，对这些受体下游的信号元件知之甚少，这些信号元件对Vps33B突变体的超敏反应至关重要。在这里，我们发现p38b MAP激酶有助于增强缺乏Vps33B的果蝇的炎症反应。p38b MAPK的缺失减少了炎症反应的增强，延长了感染Vps33B缺陷果蝇的存活时间。p38 MAPK的功能不仅限于其在PGRP-LC受体下游的促炎作用，p38还调节PGRP-LC的内体运输和细菌的吞噬。组成型活性p38b MAPK的表达，而非显性阴性p38b MAPK的表达，可增强细胞内吞吞PGRP-LC受体或被吞噬细菌的积累。此外，p38 MAPK是诱导巨噬细胞增多症所必需的，这是免疫受体下调的另一种途径。综上所述，我们的数据表明p38 MAPK激活了多种途径，可以促进ARC综合征中先天免疫信号的失调。
Loss of the Arthrogryposis-Renal dysfunction-Cholestasis (ARC) syndrome-linked Vps33B protein results in exaggerated inflammatory responses upon activation of receptors of the innate immune system in both vertebrates and flies. However, little is known about the signaling elements downstream of these receptors that are critical for the hypersensitivity of Vps33B mutants. Here, we show that p38b MAP kinase contributes to the enhanced inflammatory responses in flies lacking Vps33B. Loss of p38b MAPK reduces enhanced inflammatory responses and prolongs the survival of infected Vps33B deficient flies. The function of p38 MAPK is not limited to its pro-inflammatory effects downstream of the PGRP-LC receptor as p38 also modulates endosomal trafficking of PGRP-LC and phagocytosis of bacteria. Expression of constitutively active p38b MAPK, but not dominant negative p38b MAPK enhances accumulation of endocytosed PGRP-LC receptors or phagocytosed bacteria within cells. Moreover, p38 MAPK is required for induction of macropinocytosis, an alternate pathway for the downregulation of immune receptors. Together, our data indicate that p38 MAPK activates multiple pathways that can contribute to the dysregulation of innate immune signaling in ARC syndrome.
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影响因子：
56.9
作者：
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