GRP75 as a functional element of cholix transcytosis.

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Keyi Liu, Tom Hunter, Alistair Taverner, Kevin Yin, Julia MacKay, Kate Colebrook, Morgan Correia, Amandine Rapp, Randall J Mrsny
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引用次数: 2

Abstract

Cholix (Chx) is secreted by non-pandemic strains of Vibrio cholerae in the intestinal lumen. For this exotoxin to induce cell death in non-polarized cells in the intestinal lamina propria, it must traverse the epithelium in the fully intact form. We identified host cell elements in polarized enterocytes associated with Chx endocytosis and apical to basal (A→B) vesicular transcytosis. This pathway overcomes endogenous mechanisms of apical vesicle recycling and lysosomal targeting by interacting with several host cell proteins that include the 75 kDa glucose-regulated protein (GRP75). Apical endocytosis of Chx appears to involve the single membrane spanning protein TMEM132A, and interaction with furin before it engages GRP75 in apical vesicular structures. Sorting within these apical vesicles results in Chx being trafficked to the basal region of cells in association with the Lectin, Mannose Binding 1 protein LMAN1. In this location, Chx interacts with the basement membrane-specific heparan sulfate proteoglycan perlecan in recycling endosomes prior to its release from this basal vesicular compartment to enter the underlying lamina propria. While the furin and LMAN1 elements of this Chx transcytosis pathway undergo cellular redistribution that are reflective of the polarity shifts noted for coatamer complexes COPI and COPII, GRP75 and perlecan fail to show these dramatic rearrangements. Together, these data define essential steps in the A→B transcytosis pathway accessed by Chx to reach the intestinal lamina propria where it can engage and intoxicate certain non-polarized cells.

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GRP75作为胆囊炎胞吞作用的功能因子。
Chx是由非大流行霍乱弧菌菌株在肠道内分泌的。为了使这种外毒素诱导肠固有层非极化细胞死亡,它必须以完全完整的形式穿过上皮。我们在极化肠细胞中发现了与Chx内吞作用和从顶部到底部(A→B)囊泡胞吞作用相关的宿主细胞元件。该途径通过与包括75 kDa葡萄糖调节蛋白(GRP75)在内的几种宿主细胞蛋白相互作用,克服了根尖囊泡循环和溶酶体靶向的内源性机制。Chx的根尖内吞作用似乎涉及单膜跨越蛋白TMEM132A,并在与GRP75参与根尖泡结构之前与furin相互作用。在这些顶端囊泡内的分选导致Chx与凝集素、甘露糖结合1蛋白LMAN1一起被运输到细胞的基底区域。在这个位置,Chx与基底膜特异性硫酸肝素蛋白聚糖perlecan相互作用,在内体从基底囊泡室释放进入下层固有层之前,再循环内体。虽然这种Chx胞吞途径的furin和LMAN1元件经历细胞重分布,反映了涂层复合物COPI和COPII的极性变化,但GRP75和perlecan没有表现出这些戏剧性的重排。总之,这些数据定义了Chx到达肠固有层的A→B胞吞途径的基本步骤,Chx可以在肠固有层参与和中毒某些非极化细胞。
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来源期刊
Tissue Barriers
Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.60
自引率
6.50%
发文量
25
期刊介绍: Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.
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