Elucidation of the regulatory mechanisms for balancing TLR7 and TLR9 responses by UNC93b1

阐明 UNC93b1 平衡 TLR7 和 TLR9 反应的调节机制

• 批准号: 21590528
• 负责人: SAITOH Shin-ichiroh
• 金额: $ 3.08万
• 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: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590528/
• 关键词: Toll-like receptor; 核酸認識; ノックインマウス; LC-Ms/Ms解析; TLR7; TLR9; 自然免疫; 自己免疫疾患; Toll-like Receptor; Unc93b1; UNC93b1; LC-MS; MS解析; Yeast Two Hybrid

We revealed that we have a mechanism for balancing TLR9 response as a DNA sensor and TLR7 response as a RNA sensor. We identified the PDZ binding domain in N terminal region of UNC93b1 regulating the balance. We established knock-in mice for disrupting the PDZ binding domain by single amino-acid substitution. TLR7 response significantly increases and TLR9 response decreases in the Knock-in mice. Around 75% of the Knock-in mice died within a year. The mice have systemic inflammation with splenomegaly. TLR7 knockout and UNC93b1 knock-in mice are no phenotype. This result indicates that TLR7 plays an important role for the systemic inflammation. We revealed the importance of negative regulatory mechanism via PDZ binding domain in UNC93b1 in vivo. We also identified a functional UNC93b1 binding protein to regulate TLR7 and TLR9 responses.

我们发现我们有一种平衡作为 DNA 传感器的 TLR9 响应和作为 RNA 传感器的 TLR7 响应的机制。我们确定了 UNC93b1 N 末端区域的 PDZ 结合域调节平衡。我们建立了敲入小鼠，通过单个氨基酸取代来破坏 PDZ 结合域。在敲入小鼠中，TLR7 反应显着增加，而 TLR9 反应减少。大约 75% 的敲入小鼠在一年内死亡。小鼠出现全身炎症并伴有脾肿大。 TLR7敲除和UNC93b1敲入小鼠均无表型。该结果表明TLR7在全身炎症中发挥重要作用。我们揭示了体内 UNC93b1 中通过 PDZ 结合域负调控机制的重要性。我们还鉴定了一种功能性 UNC93b1 结合蛋白来调节 TLR7 和 TLR9 反应。

项目成果

UNC93b1を介したToll-like receptor (TLR)7と9の制御

通过 UNC93b1 调节 Toll 样受体 (TLR) 7 和 9

• 发表时间: 2009
• 作者: 明里宏文;齋藤伸一郎
• 通讯作者: 齋藤伸一郎

Unc93B1遺伝子改変マウスの確立とその応用

Unc93B1转基因小鼠的建立及其应用

• 发表时间: 2010

UNC93b1を介したToll-like receptor(TLR) 7と9の制御

通过 UNC93b1 调节 Toll 样受体 (TLR) 7 和 9

• 发表时间: 2009

幕張メッセタイトル: TRAMの分子動態と抗原提示プラットホーム

幕张展览馆标题：TRAM分子动力学和抗原呈递平台

• 发表时间: 2011
• 作者: 明里宏文;谷村奈津子
• 通讯作者: 谷村奈津子

Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing.

• DOI: 10.1084/jem.20082316
• 发表时间: 2009-06-08
• 期刊: The Journal of experimental medicine
• 作者: Fukui R;Saitoh S;Matsumoto F;Kozuka-Hata H;Oyama M;Tabeta K;Beutler B;Miyake K
• 通讯作者: Miyake K