蛋白分离酶VCP/p97通过调节SYK活化促进宿主的抗真菌防御。

IF 5.5 1区 医学 Q1 MICROBIOLOGY PLoS Pathogens Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012674
Zhugui Shao, Li Wang, Limin Cao, Tian Chen, Xin-Ming Jia, Wanwei Sun, Chengjiang Gao, Hui Xiao
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引用次数: 0

摘要

C型凝集素受体(CLR)对于宿主抵御真菌感染至关重要。然而,全面了解 CLR 信号转导的分子基础仍是一项正在进行的工作。在此,我们寻找了 Dectin-1 信号转导中尚未确定的酪氨酸磷酸化蛋白,并将应激反应蛋白含缬氨酸蛋白(VCP)/p97 与 Dectin-1 信号转导联系起来。敲除 VCP 的表达或化学抑制 VCP 的分离酶活性可抑制 Dectin-1 在 BMDMs 和 BMDCs 中引发的 SYK 激活,从而减少 TNF-α、IL-6 和 CXCL1 等促炎细胞因子/趋化因子的表达。生化分析表明,在 Dectin-1 连接后,VCP 及其辅助因子 UFD1 与 SYK 及其磷酸酶 SHP-1 形成复合物,而敲除 VCP 会导致 SYK 和 SHP-1 的关联更加突出。此外,SHP-1在Dectin-1激活后会被多泛素化,而VCP或UFD1的过表达会加速SHP-1的降解。可以想象,VCP可能通过将泛素化的SHP-1从SYK复合物中拉出降解来促进Dectin-1的信号转导。最后,基因消减中性粒细胞和巨噬细胞中的 VCP 会使小鼠极易受到白色念珠菌的感染,通过注射 VCP 抑制剂也能观察到这一现象。这些结果共同证明,VCP 是一种以前未被重视的 Dectin-1 通路信号转导子,也是抗真菌防御的一个重要组成部分,并提出了一种调节 SYK 激活的新机制。
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The protein segregase VCP/p97 promotes host antifungal defense via regulation of SYK activation.

C-type lectin receptors (CLRs) are essential to execute host defense against fungal infection. Nevertheless, a comprehensive understanding of the molecular underpinnings of CLR signaling remains a work in progress. Here, we searched for yet-to-be-identified tyrosine-phosphorylated proteins in Dectin-1 signaling and linked the stress-response protein valosin containing protein (VCP)/p97 to Dectin-1 signaling. Knockdown of VCP expression or chemical inhibition of VCP's segregase activity dampened Dectin-1-elicited SYK activation in BMDMs and BMDCs, leading to attenuated expression of proinflammatory cytokines/chemokines such as TNF-α, IL-6 and CXCL1. Biochemical analyses demonstrated that VCP and its cofactor UFD1 form a complex with SYK and its phosphatase SHP-1 following Dectin-1 ligation, and knockdown of VCP led to a more prominent SYK and SHP-1 association. Further, SHP-1 became polyubiquitinated upon Dectin-1 activation, and VCP or UFD1 overexpression accelerated SHP-1 degradation. Conceivably, VCP may promote Dectin-1 signaling by pulling the ubiquitinated SHP-1 out of the SYK complex for degradation. Finally, genetic ablation of VCP in the neutrophil and macrophage compartment rendered the mice highly susceptible to infection by Candida albicans, an observation also phenocopied by administering the VCP inhibitor. These results collectively demonstrate that VCP is a previously unappreciated signal transducer of the Dectin-1 pathway and a crucial component of antifungal defense, and suggest a new mechanism regulating SYK activation.

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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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