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Molecular mechanism for activation of the reactive-oxygen-species-producing phagocyte NADPH oxidase involved in host defense against microbial infections

活化产生活性氧的吞噬细胞 NADPH 氧化酶参与宿主防御微生物感染的分子机制

基本信息

批准号：
16017275
负责人：
SUMIMOTO Hideki
金额：
$ 9.6万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16017275/
关键词：
Infection Immunology Protein Signal transduction Enzyme

项目摘要

The NADPH oxidase is an enzyme that produces reactive oxygen species, which play a crucial role in host defense against microbial infections. The catalytic core of the phagocyte NADPH oxidase is membrane-integrated cytochrome b558, comprising gp91^<Phox> and p22^<Phox>. Activation of the oxidase requires stimulus-induced membrane translocation of specific adaptor proteins (p47^<Phox>, p67^<Phox>, and p40^<Phox>, each containing SH3 domain) and the small GTPase Rac. Recent studies have identified several mammalian homologues of gp91^<Phox>, presently known as Nox-family oxidases : e.g., Noxl, abundant in the colon epithelial cells, is likely involved in local host defense. In the present project, we investigated the molecular mechanism for oxidase activation, and obtained the following novel results. (1) Our biochemical analyses have revealed that, in activation of gp91^<Phox>, p47^<Phox> translocates to the membrane via both PX domain-mediated interaction with phosphoinositides and 5113 domain-mediated binding to p22^<Phox>. We have also determined the complex structure of the p47^<Phox> SH3 domains with the p22^<Phox> proline-rich region (PRR). (2) We have shown that p67^<Phox> interacts with p47^<Phox> via the C-terminal S113 domain in a novel fashion, and determined the NMR structure of a complex between the p67^<Phox> SH3 domain and the p47^<Phox> PRR. (3) We have demonstrated that p4O^<Phox> facilitates the oxidase activation by enhancing the membrane translocation of p47^<Phox> and p67^<Phox>, which effect is mediated via the PB1 domain-mediated heterodimeriztion with p67^<Phox>. (4) We have identified and cloned novel homologues of p47^<Phox> and p67^<Phox>, designated Noxol and Noxal, respectively, and shown that both proteins are required for activation of Noxl. (5) Our recent study has shown that Rac participates in Noxl activation, which is mediated via its interaction with Noxal.

NADPH氧化酶是一种产生活性氧的酶，其在宿主防御微生物感染中起关键作用。吞噬细胞NADPH氧化酶的催化核心是膜整合的细胞色素b558，包括gp91 α<Phox>和p22 α<Phox>。氧化酶的激活需要刺激诱导的特异性衔接蛋白（p47^<Phox>、p67^<Phox>和p40^<Phox>，每个都含有SH3结构域）和小GT3受体Rac的膜转位。最近的研究已经鉴定了gp91 α的几种哺乳动物同源物<Phox>，目前称为Nox家族氧化酶：例如，Noxl在结肠上皮细胞中丰富，可能参与局部宿主防御。在本项目中，我们研究了氧化酶激活的分子机制，并获得了以下新的结果。(1)我们的生物化学分析已经揭示，在gp91^的活化中<Phox>，p47^<Phox>通过PX结构域介导的与磷酸肌醇的相互作用和5113结构域介导的与p22^的结合两者易位到膜<Phox>。我们还确定了p47^ SH3<Phox>结构域与p22^<Phox>脯氨酸富集区（PRR）的复合结构。(2)我们已经证明p67^<Phox><Phox>通过C端S113结构域以一种新的方式与p47^相互作用，并确定了p67^<Phox>SH3结构域和p47^<Phox>PRR之间复合物的NMR结构。(3)我们已经证明，p4O^<Phox>通过增强p47^和p67^的膜转位来促进氧化酶活化<Phox><Phox>，这种作用是通过PB1结构域介导的与p67^的异源二聚化来介导的<Phox>。(4)我们已经鉴定并克隆了p47^和p67^的新同源物<Phox><Phox>，分别命名为Noxol和Noxal，并表明这两种蛋白质都是激活Noxl所必需的。(5)我们最近的研究表明，Rac参与Noxl激活，这是通过其与Noxal的相互作用介导的。

项目成果

期刊论文数量（246）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased expression of NAD(P)H oxidase in islets of animal modeles of type II diabetes and its improvement by an AT1 receptor antagonist.

II 型糖尿病动物模型胰岛中 NAD(P)H 氧化酶的表达增加及其通过 AT1 受体拮抗剂的改善。

DOI：
发表时间：
2005
期刊：
Biochem.Biophys.Res.Commun 332
影响因子：
0
作者：
Nakayama;M.;et al.
通讯作者：
et al.

Cloning of rat p4^phox and comparison with human p47^phox.

大鼠 p4^phox 的克隆并与人 p47^phox 进行比较。

DOI：
发表时间：
2005
期刊：
DNA Seq. 16
影响因子：
0
作者：
Tanabe;M.;et al.
通讯作者：
et al.

Isoform- specific membrane targeting mechanism of Rac during FcyR-mediated phagocytosis : positive charge-dependent and independent targeting mechanism of Rac to the phagosome.

FcγR介导的吞噬作用过程中Rac的亚型特异性膜靶向机制：Rac对吞噬体的正电荷依赖性和独立靶向机制。

DOI：
发表时间：
2005
期刊：
J. Immunat 175
影响因子：
0
作者：
Ueyama;T.;Eto;M.;Kami;K.;Tatsuno;T.;Kobayashi;T.;Shirai;Y.;Lennartz;M.R.;Takeya;R.;Sumimoto;H.;Saito;N.
通讯作者：
N.

111,13C and 15N resonance assignments of the backbone and methyl groups of the 24 kDa tetratricopeptide repeat domain in p67Phox.

p67Phox 中 24 kDa 四肽重复结构域的主链和甲基的 111,13C 和 15N 共振分配。