Functional Analysis of novel molecule, PRAT4 which associated with TLR4

与TLR4相关的新分子PRAT4的功能分析

• 批准号: 18590469
• 负责人: AKASHI Sachiko
• 金额: $ 2.57万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590469/
• 关键词: TLR; PRAT4A; LPS

Recently we have found a novel ER-resident chaperone which was discovered through co-immunoprecipitation with TLR4, PRAT4A. Although initially found as a TLR4-binding chaperone, and thusly named, PRAT4A also associates with TLR1. PRAT4A is shown to be indispensable for cell-surface expression of these TLRs. A consequence of the inability to traffic TLR4/TLR1, in the absence of PRAT4A, is that cytokine production in response to TLR4/TLR1 ligands is significantly reduced.PRAT4A not only regulates the response of cell-surface TLR but also intracellular TLR. In the absence of PRAT4A, the response to TLR9 ligand is completely abolished. Upon CpG-B stimulation, TLR9 was reported to redistribute from the ER to CpG-B DNA-containing lysosomes. By contrast, TLR9 in PRAT4A-silenced cells have been shown to co-localize with ER marker but not with a lysosome marker or CpG-B-Rhodamine even after CpG-B stimulation. These types of experiments demonstrate a requirement for PRAT4A in ligand-induced relo … More cation/trafficking of TLR9 from the ER to lysosomal compartments.An interesting character of PRAT4A is that PRAT4A dependency varies with each TLR. TLR7 or TLR9 mediated responses are completely dependent on PRAT4A, whereas TLR3, another nucleic acid-sensing TLR, has been shown to respond to poly (I:C) stimulation in the absence of PRAT4A. On the other hand, the responses of cell-surface TLRs seem partially dependent on PRAT4A.Another unique character of PRAT4A is that it is indispensable for induction the endotoxin shock. Experiments have shown that PRAT4A^<-/-> BM chimeric mice are able to withstand toxic shock, in comparison to chimeric WT controls, further experiments revealed that serum cytokine levels also follow a PRAT4A-dependency. Although it remains unclear whether the lower production of cytokines is the reason for survival in PRAT4A^<-/-> BM chimeric mice or not, these results open exciting avenues of further research and the possibility that PRAT4A may become a useful target for therapeutic intervention. Less

最近我们发现了一种新的内质网驻留伴侣，它是通过与 TLR4 共免疫沉淀发现的，虽然最初被发现是 TLR4 结合伴侣，并因此命名，但 PRAT4A 也与这些 TLR A 的表面表达相关。在缺乏 PRAT4A 的情况下，无法运输 TLR4/TLR1 的后果是细胞因子对 TLR4/TLR1 配体的反应显着减少。PRAT4A 不仅调节细胞表面 TLR 的反应，而且还调节细胞内 TLR。在没有 PRAT4A 的情况下，TLR9 配体的反应在 CpG-B 刺激后完全消失。据报道，TLR9 从 ER 重新分配到含有 CpG-B DNA 的溶酶体，而 PRAT4A 沉默的细胞中的 TLR9 已被重新分配。显示与 ER 标记共定位，但即使在 CpG-B 刺激后，也不与溶酶体标记或 CpG-B-罗丹明共定位。这些类型的实验表明，在配体诱导的 TLR9 阳离子/运输中需要 PRAT4A。 ER 至溶酶体区室。PRAT4A 的一个有趣特征是 PRAT4A 依赖性随每个 TLR7 或 TLR9 介导的反应而变化。 PRAT4A 和 TLR3（另一种核酸感应 TLR）已被证明在 PRAT4A 不存在的情况下对聚 (I:C) 刺激做出反应。另一方面，细胞表面 TLR 的反应似乎部分依赖于 PRAT4A。 PRAT4A的独特之处在于它对于诱导内毒素休克是不可或缺的。实验表明PRAT4A^</-> BM嵌合小鼠能够耐受毒性。与嵌合WT对照相比，进一步的实验表明血清细胞因子水平也遵循PRAT4A依赖性，尽管目前尚不清楚细胞因子的较低产量是否是PRAT4A^<-/-> BM嵌合小鼠或小鼠存活的原因。并非如此，这些结果为进一步研究开辟了令人兴奋的途径，并有可能使 PRAT4A 成为治疗干预的有用靶标。

项目成果

PRAT4AはTLRを介する自然免疫応答に必要である

TLR 介导的先天免疫反应需要 PRAT4A

• 发表时间: 2007
• 作者: Kitagawa;Y.;Kameoka;M.;Shoji-Kawata;S.;Iwabu;Y.;Mizuta;H.;Tokunaga;K.;Fujino;M.;Natori;Y.;Yura;Y. Ikuta;K.;高村(赤司)祥子
• 通讯作者: 高村(赤司)祥子

A molecule that is associated with Toll-like receptor 4 and regulates its cell surface expression

• DOI: 10.1016/j.bbrc.2005.11.123
• 发表时间: 2006-01-27
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Konno, K;Wakabayashi, Y;Miyake, K
• 通讯作者: Miyake, K

Penta-acylated lipopolisaccharide binds to murine MD-2 but does not induce the oligomerization of TLR4 required for signal transduction

五酰化脂多糖与小鼠 MD-2 结合，但不会诱导信号转导所需的 TLR4 寡聚化

• 发表时间: 2006
• 期刊: Cell Immunol. 244
• 作者: Nakai-Murakami;C.;Shimura;M.;Kinomoto;M.;Takizawa;Y.;Tokunaga;K.;Taguchi;T.;Hoshino;S.;Miyagawa;K.;Sata;T.;Kurumizaka;H.;Yuo;A.;and Ishizaka;Y.;Tsuneyoshi N
• 通讯作者: Tsuneyoshi N

PRotein associated with Toll-like receptor 4 (PRAT4A) is a novel regulator for immune response

与 Toll 样受体 4 (PRAT4A) 相关的蛋白质是免疫反应的新型调节剂

• 发表时间: 2007
• 作者: Haga;S.;Yamamoto;N.;Nakai-Murakami;C.;Osawa;Y.;Tokunaga;K.;Sata;T.;Yamamoto;N.;Sasazuki;T.;Ishizaka;Y.;Takuma Shibata
• 通讯作者: Takuma Shibata

The identification of a novel molecule associated with TLR2

与 TLR2 相关的新分子的鉴定

• 发表时间: 2006
• 作者: Kinomoto M;Shimura M;Ishizaka Y;Sata T;Tokunaga K Differential inhibitory activities of APOBEC3 family proteins on retroviruses;LINE-1 retrotransposon.;SHIBATA Takuma;KUSUMOTO Yutaka
• 通讯作者: KUSUMOTO Yutaka