组织蛋白酶是Toll样受体9应答所必需的。
Cathepsins are required for Toll-like receptor 9 responses.
作者信息
Matsumoto Fumi, Saitoh Shin-Ichiroh, Fukui Ryutaroh, Kobayashi Toshihiko, Tanimura Natsuko, Konno Kazunori, Kusumoto Yutaka, Akashi-Takamura Sachiko, Miyake Kensuke
机构信息
Division of Infectious Genetics, The Institute of Medical Science, Department of Microbiology and Immunology, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan.
出版信息
Biochem Biophys Res Commun. 2008 Mar 14;367(3):693-9. doi: 10.1016/j.bbrc.2007.12.130. Epub 2007 Dec 31.
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 downregulated interaction of CpG-B with TLR9 in 293T cells. These results suggest roles for cathepsins in DNA recognition by TLR9.
Toll样受体（TLR）可识别多种微生物产物并激活防御反应。TLR2/4对病原体的感知需要辅助分子，而对于TLR9识别DNA所需的分子却知之甚少。微生物被内吞后，其DNA会暴露出来并在溶酶体中被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反应方面存在缺陷。用Ba/F3进行功能克隆鉴定出组织蛋白酶B/L是TLR9反应所需的分子。蛋白酶活性对互补效应至关重要。组织蛋白酶S或F也能赋予TLR9反应，但组织蛋白酶H则不能。组织蛋白酶B/L抑制剂明显下调了TLR9依赖性B细胞增殖和CD86上调。组织蛋白酶B抑制剂下调了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。
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