Analysis of phagosome-associated protein (TACO) involved in the intracellular infection of mycobacterium

参与分枝杆菌胞内感染的吞噬体相关蛋白（TACO）分析

• 批准号: 13670207
• 负责人: NAITO Makoto
• 金额: $ 2.24万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670207/
• 关键词: macrophages; TACO; intracellular transport protein; BCG; Listeria; transgenic mice

Mycobacteria are intracellular pathogens that can survive within macrophage phagosomes. The molecular mechanisms involved in mycobacterial entry are still poorly characterized. We have identified a WD repeat host protein that was recruited to and actively retained on phagosomes by living, but not dead, mycobacteria. This protein, termed TACO, represents a component of the phagosome coat that is normally released prior to phagosome fusion with or maturation into lysosomes. In macrophages lacking TACO, mycobacteria were readily transported to lysosomes followed by their degradation. Expression of TACO in nonmacrophages prevented lysosomal delivery of mycobacteria and prolonged their intracellular survival. Active retention of TACO on phagosomes by living mycobacteria thus represents a mechanism preventing cargo delivery to lysosomes, allowing mycobacteria to survive within macrophages.We have examined Listeria monocytogenesinfection murine models. As demonstrated by BCGinfection models, … More the expression of TACO was induced in macrophages by Listeria infection, suggesting that TACO is involved in the infection by intracellular parasites such as Listeria as well as BCG. However, IFN-gamma stimulation facilitated expression of TACO, indicating that upregulation of TACO expression might be secondary to inflammatory changes. Therefore we focused on BCGinfection models.We employed TACOtransgenic mice produced by our collaborator, Prof. J Peters in Basel University. Previous data suggested that enhanced expression of TACO may downregulate phagosome-lysosome fusion and may provide disadvantageous effects for infection. Unexpectedly, the numbers of hepatic granulomas in TACO transgenic mice were smaller than those in wild type mice, indicating that transgenic mice were more resistant to BCG infection. Because TACO is a coat protein of phagosomes and closely related to actin fibers, TACO may be involved in not only in the transport of phagosomes but also endocytic function of macrophages. Further studies are undertaken to clarify the function of TACO. Less

分枝杆菌是可以在巨噬细胞吞噬体内存活的细胞内病原体。参与分枝杆菌进入的分子机制仍然很差的特点。我们已经确定了WD重复宿主蛋白，该蛋白被活的而不是死的分枝杆菌招募并积极保留在吞噬体上。这种蛋白质称为TACO，代表吞噬体外壳的一种组分，其通常在吞噬体与溶酶体融合或成熟为溶酶体之前释放。在缺乏TACO的巨噬细胞中，分枝杆菌很容易被转运到溶酶体，然后被降解。非巨噬细胞中TACO的表达阻止了分枝杆菌的溶酶体递送并延长了其细胞内存活。TACO对活分枝杆菌吞噬体的主动保留，因此代表了一种机制，防止货物运送到溶酶体，使分枝杆菌在macrophage.We内生存检查李斯特菌monocytogenesinfection小鼠模型。如BCG感染模型所示， ...更多信息 李斯特菌感染在巨噬细胞中诱导TACO的表达，表明TACO参与细胞内寄生虫如李斯特菌以及BCG的感染。然而，IFN-γ刺激促进了TACO的表达，表明TACO表达的上调可能继发于炎症变化。因此，我们将重点放在BCG感染模型上，我们使用了我们的合作者巴塞尔大学的J Peters教授生产的转TACO基因小鼠。以前的数据表明，TACO的表达增强可能下调吞噬体-溶酶体融合，并可能对感染产生不利影响。出乎意料的是，TACO转基因小鼠的肝脏肉芽肿数量比野生型小鼠少，表明转基因小鼠对BCG感染更具抵抗力。由于TACO是吞噬体的外壳蛋白，且与肌动蛋白纤维密切相关，因此TACO不仅可能参与吞噬体的转运，还可能参与巨噬细胞的内吞功能。进一步的研究正在进行，以澄清TACO的功能。少

项目成果

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Saiura A等人：“在没有干扰素-γ的情况下，通过DNA微阵列检测小鼠心脏同种异体移植物中一组趋化因子基因的上调”，移植73(9)。

Tanaka T, et al.: "The generation of monoclonal antibodies against human peroxisome proliferator-activated receptors (PPARs)"Atheroscl Thromb. 9 (5). 233-242 (2002)

Tanaka T 等人：“针对人过氧化物酶体增殖物激活受体 (PPAR) 的单克隆抗体的生成”动脉粥样硬化血栓。

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Kuwata K 等人：“AIM 抑制棒状杆菌诱导的小鼠肉芽肿形成中 T 细胞和 NKT 细胞的凋亡”Am J Pathol。

Yoneyama H, Matsuno K, Zhang Y, Murai M, Itakura M, et al.: "Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease"J Exp Med. 193(1). 35-49 (2001)

Yoneyama H、Matsuno K、Zhang Y、Murai M、Itakura M 等人：“肉芽肿性肝病中循环树突状细胞前体趋化因子的调节以及汇管相关淋巴组织的形成”J Exp Med。

Saiura A et al.: "Detection of an up-regulation of a group of chemokine geness in murine cardiac allograft in the absence of interferon-γ by means of DNA microarray"Transplantation. 73(9). 1480-1486 (2002)

Saiura A 等人：“在没有干扰素-γ 的情况下，通过 DNA 微阵列检测小鼠心脏同种异体移植物中一组趋化因子基因的上调”，《移植》73(9)。