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Nature子刊:浙江大学张龙实验室阐述SUMO介导的核受体泛素化调控巨噬细胞凋亡

摘要 : 2017年6月16日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了浙江大学生命科学研究院张龙实验室题为“SUMO-triggered ubiquitination of NR4A1 controls macrophage cell death”的研究论文

2017年6月16日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了浙江大学生命科学研究院张龙实验室题为“SUMO-triggered ubiquitination of NR4A1 controls macrophage cell death”的研究论文,研究揭示SUMO介导的核受体泛素化调控巨噬细胞凋亡。张龙教授和谢枫博士为本文的共同第一作者,张龙教授和苏州大学周芳芳教授为本文的共同通讯作者。

孤核受体NR4A1(nuclear receptor subfamily4,group A,member 1)是核受体超家族中的一员,在多种生物学进程中发挥着重要的作用,包括细胞增殖、分化、凋亡、代谢和进化。孤核受体NR4A1作为环境刺激和基因表达之间联系的桥梁,能够参与调节人体一系列生理反应。NR4A1可被多种生理学信号及物理刺激诱导表达,并伴随着一个快速的降解过程。NR4A1如何被降解的分子机制,这个问题迄今还没有被研究清楚。

本文章发现核受体 NR4A1 能够发生 SUMO 修饰并且找到了两个修饰位点,SUMO 化的 NR4A1 进一步被 RNF4 多聚泛素化修饰从而降解。PIAS3能够促进 NR4A1 的 SUMO 修饰,而 SENP1 可以逆调控这个过程。NR4A1 的 SUMO 修饰能够调控炎性细胞因子与巨噬细胞凋亡。

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图:NR4A1 的 SUMO 化触发的泛素化降解

原文链接:

SUMO-triggered ubiquitination of NR4A1 controls macrophage cell death

原文摘要:

Nuclear receptor NR4A1 has been implicated as a key regulator in a wide range of pathophysiological responses. As an immediate early response gene, NR4A1 can be rapidly and potently induced by a variety of stimuli. Its induction is followed by its rapid degradation, but the mechanism by which NR4A1 is degraded remains poorly understood. Here we show that nuclear receptor NR4A1 is sumoylated by SUMO2/3. Upon poly-SUMO modification, NR4A1 can be targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. The SUMO E3 ligase PIAS3 promotes SUMOylation and polyubiquitination of NR4A1, while the SUMO protease SENP1 acts to de-conjugate SUMO. We demonstrate that this pathway is important for rapid degradation of NR4A1 after induced by stress. Moreover, we identify two SUMO modification sites in NR4A1 that are critical for maintaining low levels of NR4A1 expression. Mutation of these two NR4A1 SUMO modification sites enhances the stability of NR4A1. importantly, we show that SUMOylation is critical in controlling NR4A1 function in inflammatory cytokine signaling and controlling macrophage cell death. SUMOylation and subsequent ubiquitination on NR4A1 mitigates its inhibition of innate immune signaling, such as TNF-α- and IL-1β-induced NF-κB activation. This mechanism of sequential SUMOylation and ubiquitination, which together control the degradation of NR4A1, could be exploited for the therapeutic treatment of diseases with NR4A1 involvement.

来源: Cell Death & Differentiation 浏览次数:0

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