Aspartyl proteases target host actin nucleator complex protein to limit epithelial innate immunity.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI:10.1038/s44319-024-00270-y

Sandip Patra, Rupinder Kaur

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Abstract

Epithelial-immune cell communication is pivotal to control microbial infections. We show that glycosylphosphatidylinositol-linked aspartyl proteases (Yapsins) of the human opportunistic pathogenic yeast Candida glabrata (Cg) thwart epithelial cell (EC)-neutrophil signalling by targeting the EC protein, Arpc1B (actin nucleator Arp2/3 complex subunit), which leads to actin disassembly and impeded IL-8 secretion by ECs. Further, the diminished IL-8 secretion inhibits neutrophil migration, and protects Cg from the neutrophil-mediated killing. CgYapsin-dependent Arpc1B degradation requires Arginine-142 in Arpc1B, and leads to reduced Arpc1B-p38 MAPK interaction and downregulated p38 signalling. Consistently, Arpc1B or p38 deletion promotes survival of the Cg aspartyl protease-deficient mutant in ECs. Importantly, kidneys of the protease-deficient mutant-infected mice display elevated immune cell infiltration and cytokine secretion, implicating CgYapsins in immune response suppression in vivo. Besides delineating Cg-EC interplay, our results uncover a novel target, Arpc1B, that pathogens attack to constrain the host signalling networks, and link Arpc1B mechanistically with p38 activation.

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天冬氨酰蛋白酶以宿主肌动蛋白核聚体蛋白为靶标，限制上皮细胞的先天性免疫。

上皮细胞与免疫细胞之间的通讯是控制微生物感染的关键。我们的研究表明，人类机会致病酵母光滑念珠菌（Cg）的糖基磷脂酰肌醇连接天冬氨酰蛋白酶（Yapsins）通过靶向EC蛋白Arpc1B（肌动蛋白核聚体Arp2/3复合物亚基）阻断了上皮细胞（EC）-中性粒细胞的信号传导，从而导致肌动蛋白解体并阻碍EC分泌IL-8。此外，IL-8 分泌的减少抑制了中性粒细胞的迁移，并保护 Cg 免受中性粒细胞介导的杀伤。CgYapsin依赖的Arpc1B降解需要Arpc1B中的精氨酸-142，并导致Arpc1B-p38 MAPK相互作用减少和p38信号下调。一致的是，Arpc1B 或 p38 的缺失会促进 EC 中 Cg 天冬氨酰蛋白酶缺陷突变体的存活。重要的是，蛋白酶缺陷突变体感染小鼠的肾脏显示出免疫细胞浸润和细胞因子分泌增加，这表明 CgYapsins 与体内免疫反应抑制有关。除了描述 Cg-EC 相互作用外，我们的研究结果还发现了病原体攻击以限制宿主信号网络的新靶点 Arpc1B，并从机制上将 Arpc1B 与 p38 激活联系起来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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