Organization of the integrin LFA-1 in nanoclusters regulates its activity
Organization of the integrin LFA-1 in nanoclusters regulates its activity
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DOI：
10.1091/mbc.e05-12-1098
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发表时间：
2006-10-01
影响因子：
3.3
通讯作者：
Figdor, Carl G.
中科院分区：
文献类型：
--
作者：
Cambi, Alessandra;Joosten, Ben;Figdor, Carl G.
β2-整合素LFA-1促进单核细胞(MOS)外渗到底层组织，在那里MOS可以分化为树突状细胞(DC)。尽管DC表达LFA-1，但与MO不同，它们不能与ICAM-1结合。我们推测，DC质膜上整合素结构的改变可能导致这种效应，并研究了LFA-1在MOS和DC上的膜结构与功能的关系。LFA-1表面分布的高分辨率图谱显示，在MOS上，LFA-1功能与定义良好的纳米团簇(直径100-150 nm)中的分布有关。有趣的是，这些纳米簇中的一部分含有表达特定激活依赖的L16表位的启动的LFA-1分子。MO-T细胞结合物的实时成像显示，只有这些启动的纳米簇被动态招募到细胞界面，形成微米级的参与配体结合并连接到Talin的组件。我们的结论是，除了亲和力调节外，LFA-1的功能至少受三种不同的亲和力模式控制：随机分布的非活性分子，明确定义的配体无关的主动纳米簇，以及配体触发的微米级大簇。
The beta 2-integrin LFA-1 facilitates extravasation of monocytes (MOs) into the underlying tissues, where MOs can differentiate into dendritic cells (DCs). Although DCs express LFA-1, unlike MOs, they cannot bind to ICAM-1. We hypothesized that an altered integrin organization on the DC plasma membrane might cause this effect and investigated the relationship between membrane organization and function of LFA-1 on MOs and DCs. High-resolution mapping of LFA-1 surface distribution revealed that on MOs LFA-1 function is associated with a distribution in well-defined nanoclusters (100-150-nm diameter). Interestingly, a fraction of these nanoclusters contains primed LFA-1 molecules expressing the specific activation-dependent L16-epitope. Live imaging of MO-T-cell conjugates showed that only these primed nanoclusters are dynamically recruited to the cellular interface forming micrometer-sized assemblies engaged in ligand binding and linked to talin. We conclude that besides affinity regulation, LFA-1 function is controlled by at least three different avidity patterns: random distributed inactive molecules, well-defined ligand-independent proactive nanoclusters, and ligand-triggered micrometer-sized macroclusters.