Characterization of DC-SIGN/R interaction with human immunodeficiency virus type 1 gp120 and ICAM molecules favors the receptor's role as an antigen-capturing rather than an adhesion receptor
Characterization of DC-SIGN/R interaction with human immunodeficiency virus type 1 gp120 and ICAM molecules favors the receptor's role as an antigen-capturing rather than an adhesion receptor
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DOI：
10.1128/jvi.79.8.4589-4598.2005
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发表时间：
2005-04-01
影响因子：
5.4
通讯作者：
Sun, PD
中科院分区：
文献类型：
--
作者：
Snyder, GA;Ford, J;Sun, PD
树突状细胞（DC）特异性细胞间粘附分子3（ICAM-3）抓取非整合素结合受体（DC-SIGN）被证明与人类免疫缺陷病毒1型（HIV-1）病毒包膜蛋白gp 120结合，并被提出作为特洛伊木马来增强对宿主T细胞的反式病毒感染。为了更好地理解DC-SIGN和DC-SIGNR选择性结合HIV-1 gp 120的机制，我们在两种受体的重复区构建了一系列缺失突变。不同的截短受体以不同的寡聚体形式存在。没有任何重复的碳水化合物结合结构域是单体的，而完整的细胞外受体作为四聚体存在。所有重组受体保留其结合gp 120的能力。然而，解离常数，从单体受体的微摩尔值的四聚体受体的纳摩尔值，表明这些受体的重复区域有助于gp 120结合的亲合力显着不同。这种寡聚化可以提供受体选择性识别含有多种高甘露糖浓度碳水化合物的病原体的机制。相比之下，受体以亚微摩尔的亲和力结合ICAM，其与两种非特异性细胞表面糖蛋白Fc γ RIIb和Fc γ RIII的亲和力相似，并且DC-SIGNR的寡聚化未导致与ICAM-3的结合亲和力增加。这些发现表明DC-SIGN可能不能区分其他细胞表面糖蛋白与ICAM-3结合。DC-SIGN与gp 120结合的pH依赖性表明，该受体在中性pH下保留了高亲和力的gp 120结合，但在pH 5下失去了gp 120结合，这表明DC-SIGN在酸性内体区室中释放HIV的机制。我们的工作与DC-SIGN作为特洛伊木马促进HIV-1感染的功能相矛盾;相反，它支持DC-SIGN/R（指DC-SIGN和DC-SIGNR的名称）作为抗原捕获受体的功能。
The dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin binding receptor (DC-SIGN) was shown to bind human immunodeficiency virus type 1 (HIV-1) viral envelope protein gp120 and proposed to function as a Trojan horse to enhance trans-virus infection to host T cells. To better understand the mechanism by which DC-SIGN and DC-SIGNR selectively bind HIV-1 gp120, we constructed a series of deletion mutations in the repeat regions of both receptors. Different truncated receptors exist in different oligomeric forms. The carbohydrate binding domain without any repeats was monomeric, whereas the full extracellular receptors existed as tetramers. All reconstituted receptors retained their ability to bind gp120. The dissociation constant, however, differed drastically from micromolar values for the monomeric receptors to nanomolar values for the tetrameric receptors, suggesting that the repeat region of these receptors contributes to the avidity of gp120 binding. Such oligomerization may provide a mechanism for the receptor to selectively recognize pathogens containing multiple high-mannose-concentration carbohydrates. In contrast, the receptors bound to ICAMs with submicromolar affinities that are similar to those of two nonspecific cell surface glycoproteins, Fc gamma RIIb and Fc gamma RIII, and the oligomerization of DC-SIGNR resulted in no increase in binding affinity to ICAM-3. These findings suggest that DC-SIGN may not discriminate other cell surface glycoproteins from ICAM-3 binding. The pH dependence in DC-SIGN binding to gp120 showed that the receptor retained high-affinity gp120 binding at neutral pH but lost gp120 binding at pH 5, suggesting a release mechanism of HIV in the acidic endosomal compartment by DC-SIGN. Our work contradicts the function of DC-SIGN as a Trojan horse to facilitate HIV-1 infection; rather, it supports the function of DC-SIGN/R (a designation referring to both DC-SIGN and DC-SIGNR) as an antigen-capturing receptor.