S-Nitrosylation of Surfactant Protein-D Controls Inflammatory Function
S-Nitrosylation of Surfactant Protein-D Controls Inflammatory Function
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DOI：
10.1371/journal.pbio.0060266
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发表时间：
2008-11-01
期刊：
影响因子：
9.8
通讯作者：
Gow, Andrew J.
中科院分区：
文献类型：
--
作者：
Guo, Chang-Jiang;Atochina-Vasserman, Elena N.;Gow, Andrew J.
肺凝集素、表面活性蛋白A和D（SP-A和SP-D）涉及肺内先天免疫系统的调节。特别是，SP-D似乎具有促炎和抗炎信号传导功能。目前，这些功能之间的转换所涉及的分子机制仍不清楚。SP-D在其四级结构上与SP-A和聚集蛋白家族的其他成员（如C1 q）不同，因为它形成由N-末端结构域保持在一起的大的多聚体，而不是以传统的“花束”排列排列三螺旋结构域。在SP-D的疏水性N末端内有两个半胱氨酸残基，其对于多聚体组装是关键的，并且已被提出参与稳定二硫键。在这里，我们表明，这些半胱氨酸存在于十二聚体SP-D中的还原状态，并在体外和啮齿动物急性肺损伤模型中通过内源性肺源性一氧化氮（NO）形成S-亚硝基化的特异性靶点。S-亚硝基化越来越被认为是一种重要的翻译后修饰，具有信号传导作用。体内和体外S-亚硝基硫醇（SNO）-SP-D的形成导致SP-D多聚体的破坏，使得三聚体变得明显。十二聚体或三聚体的SNO-SP-D而非SP-D对巨噬细胞具有化学吸引力并诱导p38 MAPK磷酸化。SNO-SP-D的信号传导能力似乎是通过与钙网蛋白/CD 91结合来介导的。我们建议，NO控制这种肺聚集素的二分性，S-亚硝基化的翻译后修饰导致SP-D的四级结构改变，使其切换其炎症信号传导作用。这代表了对S-亚硝基化调节蛋白质功能和NO在先天免疫中的作用的新见解。
The pulmonary collectins, surfactant proteins A and D (SP-A and SP-D) have been implicated in the regulation of the innate immune system within the lung. In particular, SP-D appears to have both pro- and anti-inflammatory signaling functions. At present, the molecular mechanisms involved in switching between these functions remain unclear. SP-D differs in its quaternary structure from SP-A and the other members of the collectin family, such as C1q, in that it forms large multimers held together by the N-terminal domain, rather than aligning the triple helix domains in the traditional "bunch of flowers'' arrangement. There are two cysteine residues within the hydrophobic N terminus of SP-D that are critical for multimer assembly and have been proposed to be involved in stabilizing disulfide bonds. Here we show that these cysteines exist within the reduced state in dodecameric SP-D and form a specific target for S-nitrosylation both in vitro and by endogenous, pulmonary derived nitric oxide ( NO) within a rodent acute lung injury model. S-nitrosylation is becoming increasingly recognized as an important post-translational modification with signaling consequences. The formation of S-nitrosothiol (SNO)-SP-D both in vivo and in vitro results in a disruption of SP-D multimers such that trimers become evident. SNO-SP-D but not SP-D, either dodecameric or trimeric, is chemoattractive for macrophages and induces p38 MAPK phosphorylation. The signaling capacity of SNO-SP-D appears to be mediated by binding to calreticulin/CD91. We propose that NO controls the dichotomous nature of this pulmonary collectin and that posttranslational modification by S-nitrosylation causes quaternary structural alterations in SP-D, causing it to switch its inflammatory signaling role. This represents new insight into both the regulation of protein function by S-nitrosylation and NO's role in innate immunity.