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

分枝杆菌是一种细胞内的病原体，可以在巨噬细胞吞噬体内存活。分枝杆菌侵入的分子机制尚不清楚。我们已经确定了一种WD重复宿主蛋白，它通过活的分枝杆菌而不是死亡的分枝杆菌被招募到吞噬体内并活跃地保留在吞噬体内。这种蛋白质称为TACO，是吞噬小体外壳的一种成分，通常在吞噬小体与溶酶体融合或成熟进入溶酶体之前释放。在缺乏TACO的巨噬细胞中，分枝杆菌很容易被运送到溶酶体，然后被降解。在非巨噬细胞中表达Taco可阻止分枝杆菌溶酶体递送，延长其细胞内存活时间。因此，活的分枝杆菌将TACO主动滞留在吞噬小体上，这是一种阻止货物运送到溶酶体的机制，允许分枝杆菌在巨噬细胞内生存。我们研究了单核细胞增多性李斯特氏菌感染小鼠的模型。正如BCG感染模型所证明的那样，…更多的TACO被李斯特菌感染巨噬细胞诱导表达，提示TACO参与了李斯特菌和卡介苗等细胞内寄生虫的感染。然而，干扰素-γ刺激促进了TACO的表达，表明TACO的表达上调可能是炎症变化的次要因素。因此，我们将重点放在了BCG感染模型上。我们使用了我们的合作者、巴塞尔大学的J·彼得斯教授培育的TACO转基因小鼠。以往的研究表明，TACO的表达增强可能下调吞噬小体-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，这表明转基因小鼠对卡介苗感染具有更强的抵抗力。由于TACO是吞噬小体的外壳蛋白，与肌动蛋白纤维关系密切，因此TACO不仅参与吞噬小体的转运，还可能参与巨噬细胞的内吞功能。为了阐明TACO的功能，我们进行了进一步的研究。较少

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)。

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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)。