Key Points The MALT1 protease plays a dual role in allergic response. MALT1 protease activity is required for IgE-dependent mast cell cytokine production. MALT1 protease activity is required for histamine-induced endothelial permeability. The signaling protein MALT1 plays a key role in promoting NF-κB activation in Ag-stimulated lymphocytes. In this capacity, MALT1 has two functions, acting as a scaffolding protein and as a substrate-specific protease. MALT1 is also required for NF-κB–dependent induction of proinflammatory cytokines after FcεR1 stimulation in mast cells, implicating a role in allergy. Because MALT1 remains understudied in this context, we sought to investigate how MALT1 proteolytic activity contributes to the overall allergic response. We compared bone marrow–derived mast cells from MALT1 knockout (MALT1−/−) and MALT1 protease-deficient (MALTPD/PD) mice to wild-type cells. We found that MALT1−/− and MALT1PD/PD mast cells are equally impaired in cytokine production following FcεRI stimulation, indicating that MALT1 scaffolding activity is insufficient to drive the cytokine response and that MALT1 protease activity is essential. In addition to cytokine production, acute mast cell degranulation is a critical component of allergic response. Intriguingly, whereas degranulation is MALT1-independent, MALT1PD/PD mice are protected from vascular edema induced by either passive cutaneous anaphylaxis or direct challenge with histamine, a major granule component. This suggests a role for MALT1 protease activity in endothelial cells targeted by mast cell–derived vasoactive substances. Indeed, we find that in human endothelial cells, MALT1 protease is activated following histamine treatment and is required for histamine-induced permeability. We thus propose a dual role for MALT1 protease in allergic response, mediating 1) IgE-dependent mast cell cytokine production, and 2) histamine-induced endothelial permeability. This dual role indicates that therapeutic inhibitors of MALT1 protease could work synergistically to control IgE-mediated allergic disease.

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MALT1 蛋白酶通过作用于肥大细胞和内皮细胞在过敏反应中发挥双重作用

要点 MALT1 蛋白酶在过敏反应中起着双重作用。IgE 依赖性肥大细胞细胞因子的产生需要 MALT1 蛋白酶活性。组胺诱导的内皮通透性需要 MALT1 蛋白酶活性。信号蛋白 MALT1 在促进 Ag 刺激的淋巴细胞中的 NF-κB 活化中起着关键作用。在这种能力下，MALT1 具有两个功能，充当脚手架蛋白和底物特异性蛋白酶。在 FcεR1 刺激肥大细胞后，NF-κB 依赖性促炎细胞因子的诱导也需要 MALT1，这表明它在过敏中起作用。由于在这种情况下 MALT1 仍未得到充分研究，我们试图调查 MALT1 蛋白水解活性如何导致整体过敏反应。我们将来自 MALT1 敲除 (MALT1−/−) 和 MALT1 蛋白酶缺陷 (MALTPD/PD) 小鼠的骨髓来源的肥大细胞与野生型细胞进行了比较。我们发现 MALT1−/− 和 MALT1PD/PD 肥大细胞在 FcεRI 刺激后的细胞因子产生同样受损，表明 MALT1 支架活性不足以驱动细胞因子反应，MALT1 蛋白酶活性是必不可少的。除了细胞因子的产生，急性肥大细胞脱颗粒是过敏反应的重要组成部分。有趣的是，虽然脱颗粒是 MALT1 独立的，但 MALT1PD/PD 小鼠免受被动皮肤过敏反应或直接攻击组胺（一种主要颗粒成分）引起的血管水肿。这表明 MALT1 蛋白酶活性在肥大细胞衍生的血管活性物质靶向的内皮细胞中发挥作用。事实上，我们发现在人内皮细胞中，MALT1 蛋白酶在组胺处理后被激活，并且是组胺诱导的通透性所必需的。因此，我们提出 MALT1 蛋白酶在过敏反应中的双重作用，介导 1) IgE 依赖性肥大细胞细胞因子的产生，和 2) 组胺诱导的内皮通透性。这种双重作用表明 MALT1 蛋白酶的治疗性抑制剂可以协同作用以控制 IgE 介导的过敏性疾病。