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Nat Commun:陈大华等揭示果蝇天然免疫反应的新机制

来源:中科院动物所 2014-03-27 23:49

天然免疫存在于所有的多细胞生物中,是机体抵抗病原微生物的第一道防线。机体对病原微生物的天然免疫反应涉及到多基因多层次的转录、翻译和翻译后调控的复杂过程。果蝇在受到病原微生物感染时,其会通过激活天然免疫信号途径分泌许多抗菌肽分子,这些分子分泌到血淋巴细胞后能杀死入侵的病原微生物。Toll信号通路是目前了解最多的果蝇抗菌肽产生的一条信号通路,但其具体分子调节机制仍不完全清楚。

为了挖掘发现调控果蝇天然免疫Toll信号通路的E3连接酶,阐明这些调控因子是通过影响哪些关键分子来参与果蝇的天然免疫Toll信号调控的,由中科院动物研究所孙钦秒研究员和陈大华研究员领导的研究团队建立了一种大通量快速筛选方法,通过对预测的含RING结构域的进行筛选,发现pellino基因可能负调控Toll信号通路。进一步遗传学、生物化学和细胞生物学的研究发现,Pellino E3泛素连接酶能够与细胞质膜蛋白MyD88发生相互作用,并被其CTE结构域招募定位到质膜上,反过来调控MyD88蛋白的泛素化,并降解MyD88蛋白,从而实现对Toll途径的负调控作用。该研究工作揭示膜蛋白MyD88在细胞质膜上与Pellino E3连接酶形成负反馈调控环,从而决定Toll信号通路转导的鲁棒性的新机制。

该文章于2014年3月17日发表在Nature Communications杂志上。(生物谷Bioon.com)

生物谷推荐的英文摘要:

Nature Communications    doi:10.1038/ncomms4458Cell-surface localization of Pellino antagonizes Toll-mediated innate immune signalling by controlling MyD88 turnover in Drosophila

Innate immunity mediated by Toll signalling has been extensively studied, but how Toll signalling is precisely controlled in balancing innate immune responses remains poorly understood. It was reported that the plasma membrane localization of Drosophila MyD88 is necessary for the recruitment of cytosolic adaptor Tube to the cell surface, thus contributing to Toll signalling transduction. Here we demonstrate that Drosophila Pellino functions as a negative regulator in Toll-mediated signalling. We show that Pellino accumulates at the plasma membrane upon the activation of Toll signalling in a MyD88-dependent manner. Moreover, we find that Pellino is associated with MyD88 via its CTE domain, which is necessary and sufficient to promote Pellino accumulation at the plasma membrane where it targets MyD88 for ubiquitination and degradation. Collectively, our study uncovers a mechanism by which a feedback regulatory loop involving MyD88 and Pellino controls Toll-mediated signalling, thereby maintaining homeostasis of host innate immunity.

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