Entamoeba histolytica phagocytosis of human erythrocytes involves PATMK, a member of the transmembrane kinase family.
Entamoeba histolytica phagocytosis of human erythrocytes involves PATMK, a member of the transmembrane kinase family.
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DOI：
10.1371/journal.ppat.0040008
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发表时间：
2008-01
期刊：
影响因子：
6.7
通讯作者：
Petri WA Jr
中科院分区：
文献类型：
--
作者：
Boettner DR;Huston CD;Linford AS;Buss SN;Houpt E;Sherman NE;Petri WA Jr
溶组织内阿米巴是阿米巴结肠炎和肝脓肿的病因。这种寄生虫会诱导宿主细胞凋亡，并利用暴露的配体（例如磷脂酰丝氨酸）吞噬凋亡的尸体并侵入宿主组织的更深处。这项工作的目的是鉴定参与识别和摄取死细胞的阿米巴蛋白。跨膜激酶家族的一个成员，吞噬体相关 TMK96 (PATMK)，是在早期吞噬体蛋白的蛋白质组学筛选中被鉴定出来的。针对 PATMK 产生的抗肽亲和纯化抗体表明，它是一种在滋养体表面表达的 I 型整合膜蛋白，并且与人红细胞在接触位点共定位。 PATMK 在体外吞噬红细胞作用中的作用通过以下方法证明：(i) 将阿米巴原虫与抗 PATMK 抗体一起孵育； (ii) 使用新型 shRNA 表达系统敲低 PATMK mRNA； (iii) PATMK 羧基截短的表达 (PATMKΔ932)。 PATMKΔ932的羧基截短的表达还导致溶组织内阿米巴在阿米巴病肠道模型中建立感染的能力的特异性降低，但是这些阿米巴在直接注射到肝脏中时保留了引起肝脓肿的能力。总之，PATMK 被确定为 TMK 家族的成员，参与红细胞吞噬作用，并且是肠道感染所必需的。寄生虫溶组织内阿米巴与人体细胞相互作用是一个高度有序的过程。通过寄生虫凝集素的粘附在几秒钟内就会被杀死，阿米巴只吞下尸体而不是活细胞。这一过程对于发病机制至关重要，临床医生利用摄入的红细胞来识别溶组织内阿米巴并将其与肠道无害的共生阿米巴原虫区分开来。我们假设，鉴定与摄入尸体有关的分子可能有助于了解阿米巴如何引起结肠炎。我们鉴定出跨膜激酶家族的一个成员是吞噬体的早期组成部分。抑制这种激酶可以阻止红细胞的摄取，并防止阿米巴定植和侵入肠道。显性失活寄生虫对引起肝脓肿没有影响，表明解剖部位之间的发病机制不同。未来对噬红细胞作用中跨膜激酶的研究可能有助于了解阿米巴如何定植和侵入肠道，最终目标是预防疾病。
Entamoeba histolytica is the cause of amebic colitis and liver abscess. This parasite induces apoptosis in host cells and utilizes exposed ligands such as phosphatidylserine to ingest the apoptotic corpses and invade deeper into host tissue. The purpose of this work was to identify amebic proteins involved in the recognition and ingestion of dead cells. A member of the transmembrane kinase family, phagosome-associated TMK96 (PATMK), was identified in a proteomic screen for early phagosomal proteins. Anti-peptide affinity-purified antibody produced against PATMK demonstrated that it was a type I integral membrane protein that was expressed on the trophozoite surface, and that co-localized with human erythrocytes at the site of contact. The role of PATMK in erythrophagocytosis in vitro was demonstrated by: (i) incubation of ameba with anti-PATMK antibodies; (ii) PATMK mRNA knock-down using a novel shRNA expression system; and (iii) expression of a carboxy-truncation of PATMK (PATMKΔ932). Expression of the carboxy-truncation of PATMKΔ932 also caused a specific reduction in the ability of E. histolytica to establish infection in the intestinal model of amebiasis, however these amebae retained the ability to cause hepatic abscesses when directly injected in the liver. In conclusion, PATMK was identified as a member of the TMK family that participates in erythrophagocytosis and is uniquely required for intestinal infection. There is a highly ordered process by which the parasite Entamoeba histolytica interacts with human cells. Adherence via a parasite lectin is followed in seconds by killing, with only the corpse and not a living cell ingested by the ameba. This process is so central to pathogenesis that clinicians use the presence of ingested erythrocytes to identify E. histolytica and distinguish it from harmless commensal amebae of the gut. We hypothesized that identification of molecules involved in the ingestion of the corpse might provide insight into how amebae cause colitis. We identified a member of the transmembrane kinase family as an early component of the phagosome. Inhibition of this kinase blocked red cell ingestion and prevented amebae from colonizing and invading the gut. There was no impact on dominant-negative parasites to cause liver abscess, suggesting the pathogenesis program differs between anatomic sites. Future studies of the transmembrane kinanse in erythrophagocytosis may provide insight into how amebae colonize and invade the gut, with the ultimate goal of preventing disease.
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影响因子：
2.1
作者：
Hirata, Ken K.;Que, Xuchu;Reed, Sharon L.
通讯作者：
Reed, Sharon L.
影响因子：
64.8
作者：
Loftus, B;Anderson, I;Hall, N
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Hall, N
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3.3
作者：
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Mirelman, D
影响因子：
3.4
作者：
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通讯作者：
WARHURST, DC
影响因子：
1.5
作者：
Davis, PH;Zhang, Z;Stanley, SL
通讯作者：
Stanley, SL