Hypersensitivity of Vps33B mutant flies to non-pathogenic infections is dictated by aberrant activation of p38b MAP kinase.,Traffic

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Hypersensitivity of Vps33B mutant flies to non-pathogenic infections is dictated by aberrant activation of p38b MAP kinase.
Traffic ( IF 3.6 ) Pub Date : 2020-07-16 , DOI: 10.1111/tra.12756
Jian Zhang _{1,

2} , Charles Tracy ₁ , Chandrashekhar Pasare _{3,

4} , Jinsheng Zeng ₂ , Helmut Krämer _{1,

5}

Affiliation

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 mitogen‐activated protein kinase (MAPK) reduces enhanced inflammatory responses and prolongs the survival of infected Vps33B deficient flies. The function of p38 MAPK is not limited to its proinflammatory 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.

中文翻译：

Vps33B 突变果蝇对非致病性感染的超敏反应是由 p38b MAP 激酶的异常激活决定的。

关节弯曲 - 肾功能障碍 - 胆汁淤积 (ARC) 综合征相关 Vps33B 蛋白的缺失导致脊椎动物和果蝇先天免疫系统受体激活后炎症反应加剧。然而，对这些受体下游的信号元件知之甚少，这些元件对Vps33B突变体的超敏反应至关重要。在这里，我们表明 p38b MAP 激酶有助于增强缺乏Vps33B 的果蝇的炎症反应。p38b 丝裂原活化蛋白激酶 (MAPK) 的缺失降低了增强的炎症反应并延长了受感染的Vps33B的存活苍蝇不足。p38 MAPK 的功能不仅限于其在 PGRP-LC 受体下游的促炎作用，因为 p38 还调节 PGRP-LC 的内体运输和细菌的吞噬作用。组成型活性 p38b MAPK 而非显性失活 p38b MAPK 的表达增强了细胞内内吞 PGRP-LC 受体或吞噬细菌的积累。此外，p38 MAPK 是诱导巨胞饮作用所必需的，这是一种下调免疫受体的替代途径。总之，我们的数据表明 p38 MAPK 激活了多种途径，这些途径可能导致 ARC 综合征中先天免疫信号的失调。

更新日期：2020-08-19

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