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CCL14a的N端蛋白水解对趋化因子受体CCR1和CCR5以及人巨细胞病毒编码的趋化因子受体US28活性的意义。

Significance of N-terminal proteolysis of CCL14a to activity on the chemokine receptors CCR1 and CCR5 and the human cytomegalovirus-encoded chemokine receptor US28.

作者信息

Richter Rudolf, Casarosa Paola, Ständker Ludger, Münch Jan, Springael Jean-Yves, Nijmeijer Saskia, Forssmann Wolf-Georg, Vischer Henry F, Vakili Jalal, Detheux Michel, Parmentier Marc, Leurs Rob, Smit Martine J

机构信息

Institute of Transfusion Medicine and Immune Hematology, Blood Donation Service of the German Red Cross, Frankfurt, Germany.

出版信息

J Immunol. 2009 Jul 15;183(2):1229-37. doi: 10.4049/jimmunol.0802145. Epub 2009 Jun 24.

Abstract

The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1-74) circulates in high concentrations in plasma. CCL14a(1-74) is converted into CCL14a(9-74) by the proteases urokinase-type plasminogen activator and plasmin and is a highly active agonist for the chemokine receptors CCR1 and CCR5. In this study, a new CCL14a analog, CCL14a(12-74), was isolated from blood filtrate. To elucidate the functional role of the N terminus, a panel of N-terminally truncated CCL14a analogs were tested on the receptors CCR1 to CCR5 and on the human cytomegalovirus (HCMV)-encoded chemokine receptor US28. The rank order of binding affinity to these receptors and of the activation of CCR1 and CCR5-mediated intracellular Ca(2+) concentration mobilization is CCL14a(6-74)<(7-74)<(8-74)<<(9-74) = (10-74)>>(11-74)>>(12-74). The almost identical affinities of CCL14a(7-74), CCL14a(9-74), and CCL14a(10-74) for the US28 receptor and the inhibition of US28-mediated HIV infection of 293T cells by all of the N-terminally truncated CCL14a analogs support the promiscuous nature of the viral chemokine receptor US28. In high concentrations, CCL14a(12-74) did reveal antagonistic activity on intracellular Ca(2+) concentration mobilization in CCR1- and CCR5-transfected cells, which suggests that truncation of Tyr(11) might be of significance for an efficient inactivation of CCL14a. A putative inactivation pathway of CCL14a(9-74) to CCL14a(12-74) may involve the dipeptidase CD26/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11-74), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12-74) from CCL14a(11-74). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.

摘要

CC趋化因子CCL14a在多种组织中组成性表达,其无活性的前体形式CCL14a(1 - 74)在血浆中高浓度循环。CCL14a(1 - 74)被尿激酶型纤溶酶原激活剂和纤溶酶等蛋白酶转化为CCL14a(9 - 74),并且是趋化因子受体CCR1和CCR5的高活性激动剂。在本研究中,从血液滤液中分离出一种新的CCL14a类似物CCL14a(12 - 74)。为阐明N端的功能作用,对一系列N端截短的CCL14a类似物进行了CCR1至CCR5受体以及人巨细胞病毒(HCMV)编码的趋化因子受体US28的测试。这些类似物与这些受体的结合亲和力以及CCR1和CCR5介导的细胞内Ca(2+)浓度动员激活的排序为CCL14a(6 - 74)<(7 - 74)<(8 - 74)<<(9 - 74) = (10 - 74)>>(11 - 74)>>(12 - 74)。CCL14a(7 - 74)、CCL14a(9 - 74)和CCL14a(10 - 74)对US28受体的亲和力几乎相同,并且所有N端截短的CCL14a类似物均抑制US28介导的293T细胞HIV感染,这支持了病毒趋化因子受体US28的多配体性质。在高浓度下,CCL14a(12 - 74)确实在CCR1和CCR5转染细胞中对细胞内Ca(2+)浓度动员显示出拮抗活性,这表明Tyr(11)的截短可能对CCL14a的有效失活具有重要意义。CCL14a(9 - 74)至CCL14a(12 - 74)的推定失活途径可能涉及生成CCL14a(11 - 74)的二肽酶CD26/二肽基肽酶IV(DPPIV)以及能够从CCL14a(11 - 74)生成CCL14a(12 - 74)的金属蛋白酶氨肽酶N(CD13)。我们的结果表明,CCL14a的活性可能受严格的蛋白水解激活和失活步骤调控。

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