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溶血曼海姆菌白细胞毒素的 N 端区域在哺乳动物细胞中作为线粒体靶向信号。

N-terminal region of Mannheimia haemolytica leukotoxin serves as a mitochondrial targeting signal in mammalian cells.

机构信息

Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA.

出版信息

Cell Microbiol. 2010 Jul;12(7):976-87. doi: 10.1111/j.1462-5822.2010.01445.x. Epub 2010 Jan 26.

Abstract

Mannheimia haemolytica leukotoxin (LktA) is a member of the RTX toxin family that specifically kills ruminant leukocytes. Previous studies have shown that LktA induces apoptosis in susceptible cells via a caspase-9-dependent pathway that involves binding of LktA to mitochondria. In this study, using the bioinformatics tool MitoProt II we identified an N-terminal amino acid sequence of LktA that represents a mitochondrial targeting signal (MTS). We show that expression of this sequence, as a GFP fusion protein within mammalian cells, directs GFP to mitochondria. By immunoprecipitation we demonstrate that LktA interacts with the Tom22 and Tom40 components of the translocase of the outer mitochondrial membrane (TOM), which suggests that import of this toxin into mitochondria involves a classical import pathway for endogenous proteins. We also analysed the amino acid sequences of other RTX toxins and found a MTS in the N-terminal region of Actinobacillus pleuropneumoniae ApxII and enterohaemorrhagic Escherichia coli EhxA, but not in A. pleuropneumoniae ApxI, ApxIII, Aggregatibacter actinomycetemcomitans LtxA or the haemolysin (HlyA) from uropathogenic strains of E. coli. These findings provide a new evidence for the importance of the N-terminal region in addressing certain RTX toxins to mitochondria.

摘要

溶血曼海姆菌白细胞毒素(LktA)是 RTX 毒素家族的成员,它专门杀死反刍动物的白细胞。先前的研究表明,LktA 通过一种依赖半胱天冬酶-9 的途径诱导易感细胞凋亡,该途径涉及 LktA 与线粒体的结合。在这项研究中,我们使用生物信息学工具 MitoProt II 鉴定了 LktA 的 N 端氨基酸序列,该序列代表一个线粒体靶向信号(MTS)。我们表明,该序列作为哺乳动物细胞中的 GFP 融合蛋白表达,将 GFP 引导至线粒体。通过免疫沉淀,我们证明 LktA 与外膜转位酶(TOM)的 Tom22 和 Tom40 组件相互作用,这表明这种毒素进入线粒体涉及内源性蛋白的经典导入途径。我们还分析了其他 RTX 毒素的氨基酸序列,在胸膜肺炎放线杆菌 ApxII 和肠出血性大肠杆菌 EhxA 的 N 端区域发现了一个 MTS,但在胸膜肺炎放线杆菌 ApxI、ApxIII、Aggregatibacter actinomycetemcomitans LtxA 或尿路致病性大肠杆菌的溶血素(HlyA)中没有发现。这些发现为 N 端区域在将某些 RTX 毒素靶向线粒体方面的重要性提供了新的证据。

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