Hsp70 inhibits lipopolysaccharide-induced NF-κB activation by interacting with TRAF6 and inhibiting its ubiquitination
Hsp70 inhibits lipopolysaccharide-induced NF-κB activation by interacting with TRAF6 and inhibiting its ubiquitination
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DOI：
10.1016/j.febslet.2006.04.066
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发表时间：
2006-05-29
期刊：
影响因子：
3.5
通讯作者：
Yin, Zhimin
中科院分区：
文献类型：
--
作者：
Chen, Huaqun;Wu, Yifan;Yin, Zhimin
诱导热休克蛋白 70 (Hsp70) 是在正常细胞生长和病理生理条件下维持细胞完整性的最重要的 HSP 之一。肿瘤坏死因子受体相关因子 6 (TRAF6) 是一种重要的信号转导因子，可调节多种生理和病理过程，对于激活 NF-κ B 信号通路以响应细菌脂多糖 (LPS) 至关重要。在这里，我们报道了 Hsp70 在 RAW264.7 巨噬细胞样细胞中阻止 LPS 诱导的 NF-κ B 激活的新机制。我们的结果表明，Hsp70 可以在 TRAF-C 结构域中与 TRAF6 物理结合，并阻止 TRAF6 泛素化。 LPS 的刺激以时间依赖性方式解离 Hsp70 和 TRAF6 的结合。在热休克处理以及 Hsp70 稳定转染的 RAW264.7 细胞中，Hsp70 抑制 LPS 诱导的 NF-κ B 信号级联激活，并随后降低 NOS 和 COX-2 的表达。两个 Hsp70 突变体，即具有 N 端 ATPase 结构域的 Hsp70 Delta C(1-428aa) 和具有 C 端结构域的 Hsp70C(428-642aa)，缺乏影响 TRAF6 泛素化和 TRAF6 触发的 NF-κ B 激活的能力。综上所述，这些发现表明Hsp70通过结合TRAF6并阻止其泛素化来抑制LPS诱导的NF-κB激活，从而抑制炎症介质的产生，这为分析Hsp70对LPS触发的炎症信号转导通路的影响提供了新的见解。 (c) 2006 年欧洲生化学会联合会。由 Elsevier B.V. 出版。保留所有权利。
Inducible heat shock protein 70 (Hsp70) is one of the most important HSPs for maintenance of cell integrity during normal cellular growth as well as pathophysiological conditions. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a crucial signaling transducer that regulates a diverse array of physiological and pathological processes and is essential for activating NF-kappa B signaling pathway in response to bacterial lipopolysaccharide (LPS). Here we report a novel mechanism of Hsp70 for preventing LPS-induced NF-kappa B activation in RAW264.7 macrophage-like cells. Our results show that Hsp70 can associate with TRAF6 physically in the TRAF-C domain and prevent TRAF6 ubiquitination. The stimulation of LPS dissociates the binding of Hsp70 and TRAF6 in a time-dependent manner. Hsp70 inhibits LPS-induced NF-kappa B signaling cascade activation in heat-shock treated as well as Hsp70 stable transfected RAW264.7 cells and subsequently decreases NOS and COX-2 expression. Two Hsp70 mutants, Hsp70 Delta C(1-428aa) with N-terminal ATPase domain and Hsp70C(428-642aa) with C-terminal domain, lack the ability to influence TRAF6 ubiquitination and TRAF6-triggered NF-kappa B activation. Taken together, these findings indicate that Hsp70 inhibits LPS-induced NF-kappa B activation by binding TRAF6 and preventing its ubiquitination, and results in inhibition of inflammatory mediator production, which provides a new insight for analyzing the effects of Hsp70 on LPS-triggered inflammatory signal transduction pathways. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.