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首页> 外文期刊>American Journal of Physiology >Identification of a high-mannose ICAM-1 glycoform: effects of ICAM-1 hypoglycosylation on monocyte adhesion and outside in signaling
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Identification of a high-mannose ICAM-1 glycoform: effects of ICAM-1 hypoglycosylation on monocyte adhesion and outside in signaling

机译：高甘露糖ICAM-1糖型的鉴定：ICAM-1低糖基化对单核细胞黏附和外界信号传导的影响

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Endothe-lial adhesion molecules are critical effectors of inflammation ensuring coordinated interactions that allow leukocytes to home to sites of injury. These adhesion molecules are often extensively modified posttranslationaly by the addition of N-glycans, but if, or how, these modifications contribute to the protein function remains poorly understood. Herein we show that activated endothelial cells express two distinct N-glycoforms of intercellular adhesion molecule 1 (ICAM-1) that comprise a complex N-glycoform with alpha-2,6 sialic acid present at relatively high levels and a second, less abundant and previously undescribed high-mannose glycoform (HM-ICAM-1). This novel HM-ICAM-1 glycoform was also detected in human coronary artery specimens and moreover appeared to be the dominant glycoform in vivo. Production of exclusively HM-ICAM-1 in cells by ct-mannosi-dase inhibition increased monocyte rolling and adhesion compared with mature ICAM-1 consistent with high-mannose epitopes providing leukocyte ligands. Cross-linking of ICAM-1 transmits outside-in signals that affect endothelial permeability and survival. Interestingly, cell signaling (assessed using ERK, VE-cadherin, and Akt phosphor-ylation) was maintained after cross-linking of HM-ICAM-1 compared with mature ICAM-1; however, interactions with the actin cytoskel-eton were lost with HM-ICAM-1. These findings suggest that specific ICAM-1 N-glycoforms modulate distinct aspects of the inflammatory response and identify HM-ICAM-1 as a new therapeutic target for controlling leukocyte trafficking and endothelial inflammation.
机译：内皮细胞粘附分子是炎症的重要影响因子，可确保相互协调的相互作用，使白细胞能够进入损伤部位。这些粘附分子通常在翻译后通过添加N-聚糖而被广泛修饰，但是这些修饰是否或如何有助于蛋白质功能仍然知之甚少。本文中，我们显示活化的内皮细胞表达细胞间粘附分子1（ICAM-1）的两种不同的N-糖型，其中包括一个复杂的N-糖型，其中α-2,6唾液酸的含量较高，第二个则较少，且含量较低。先前未描述的高甘露糖糖型（HM-ICAM-1）。在人的冠状动脉标本中也检测到这种新型的HM-ICAM-1糖型，而且似乎是体内的主要糖型。与成熟的ICAM-1相一致，通过ct-甘露糖苷酶抑制作用在细胞中仅产生HM-ICAM-1，与提供白细胞配体的高甘露糖表位相一致，增加了单核细胞的滚动和粘附。 ICAM-1的交联会传输从外而内的信号，从而影响内皮的通透性和存活率。有趣的是，与成熟的ICAM-1相比，HM-ICAM-1交联后，细胞信号传导（使用ERK，VE-钙粘着蛋白和Akt磷酸化评估）得以维持;但是，HM-ICAM-1与肌动蛋白细胞骨架的相互作用消失了。这些发现表明，特定的ICAM-1 N-糖型调节炎症反应的不同方面，并将HM-ICAM-1确定为控制白细胞运输和内皮炎症的新治疗靶标。

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