Cathepsins are required for toll-like receptor 9 responses
Cathepsins are required for toll-like receptor 9 responses
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DOI：
10.1016/j.bbrc.2007.12.130
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发表时间：
2008-03-14
影响因子：
3.1
通讯作者：
Miyake, Kensuke
中科院分区：
文献类型：
--
作者：
Matsumoto, Fumi;Saitoh, Shin-ichiroh;Miyake, Kensuke
Toll 样受体 (TLR) 识别多种微生物产物并激活防御反应。 TLR2/4 检测病原体需要辅助分子，而 TLR9 识别 DNA 所需的分子却知之甚少。微生物内吞后，微生物 DNA 暴露并被溶酶体中的 TLR9 识别。我们在此表明，组织蛋白酶（溶酶体半胱氨酸蛋白酶）是 TLR9 反应所必需的。尽管强制表达 TLR9，但发现细胞系 Ba/F3 在 TLR9 反应中存在缺陷。 Ba/F3 的功能克隆鉴定出组织蛋白酶 B/L 是 TLR9 反应所需的分子。蛋白酶活性对于互补作用至关重要。 TLR9 反应也由组织蛋白酶 S 或 F 赋予，但不是由组织蛋白酶 H 赋予。TLR9 依赖性 B 细胞增殖和 CD86 上调明显被组织蛋白酶 B/L 抑制剂下调。组织蛋白酶 B 抑制剂可调节 293T 细胞中 CpG-B 与 TLR9 的相互作用。这些结果表明组织蛋白酶在 TLR9 识别 DNA 中发挥作用。 (c) 2007 Elsevier Inc. 保留所有权利。
Toll-like receptors (TLR) recognize a variety of microbial products and activate defense responses. Pathogen sensing by TLR2/4 requires accessory molecules, whereas little is known about a molecule required for DNA recognition by TLR9. After endocytosis of microbes, microbial DNA is exposed and recognized by TLR9 in lysosomes. We here show that cathepsins, lysosomal cysteine proteases, are required for TLR9 responses. A cell line Ba/F3 was found to be defective in TLR9 responses despite enforced TLR9 expression. Functional cloning with Ba/F3 identified cathepsin B/L as a molecule required for TLR9 responses. The protease activity was essential for the complementing effect. TLR9 responses were also conferred by cathepsin S or F, but not by cathepsin H. TLR9-dependent B cell proliferation and CD86 upregulation were apparently downregulated by cathepsin B/L inhibitors. Cathepsin B inhibitor clownregulated interaction of CpG-B with TLR9 in 293T cells. These results suggest roles for cathepsins in DNA recognition by TLR9. (c) 2007 Elsevier Inc. All rights reserved.