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Kindlin-3 recruitment to the plasma membrane precedes high-affinity β2-integrin and neutrophil arrest from rolling.

Kindlin-3向质膜的募集先于高亲和力 β2-整联蛋白和中性粒细胞从滚动停止。

  • 影响因子:7.27
  • DOI:10.1182/blood.2019003446
  • 作者列表:"Wen L","Marki A","Roy P","McArdle S","Sun H","Fan Z","Gingras AR","Ginsberg MH","Ley K
  • 发表时间:2021-01-07
Abstract

:Integrin-mediated neutrophil adhesion starts by arrest from rolling. Activation of integrins involves conformational changes from an inactive, bent conformation to an extended conformation (E+) with high affinity for ligand binding (H+). The cytoplasmic protein kindlin-3 is necessary for leukocyte adhesion; mutations of kindlin-3 cause leukocyte adhesion deficiency type 3. Kindlin-3 binds the β2-integrin cytoplasmic tail at a site distinct from talin-1, but the molecular mechanism by which kindlin-3 activates β2-integrins is unknown. In this study, we measured the spatiotemporal dynamics of kindlin-3 and β2-integrin conformation changes during neutrophil and HL-60 cell rolling and arrest under flow. Using high-resolution quantitative dynamic footprinting microscopy and kindlin-3-fluorescent protein (FP) fusion proteins, we found that kindlin-3 was recruited to the plasma membrane in response to interleukin-8 (IL-8) before induction of the H+ β2-integrin conformation. Intravital imaging revealed that EGFP-kindlin-3-reconstituted, kindlin-3-knockout neutrophils arrest in vivo in response to CXCL1. EGFP-kindlin-3 in primary mouse neutrophils was also recruited to the plasma membrane before arrest. Upon arrest, we found small clusters of high-affinity β2-integrin molecules within large areas of membrane-proximal kindlin-3 FP. Deletion of kindlin-3 or its pleckstrin homology (PH) domain in neutrophil-like HL-60 cells completely abolished H+ β2-integrin induction. IL-8 also triggered recruitment of the isolated kindlin-3 PH domain to the plasma membrane before arrest. In summary, we showed that the kindlin-3 PH domain is necessary for recruitment to the plasma membrane, where full-length kindlin-3 is indispensable for the induction of high-affinity β2-integrin.

摘要

: 整合素介导的中性粒细胞粘附从滚动开始停止。整联蛋白的激活涉及从无活性的弯曲构象到对配体结合 (H +) 具有高亲和力的延伸构象 (E +) 的构象变化。胞质蛋白kindlin-3是白细胞粘附所必需的; kindlin-3的突变导致白细胞粘附缺陷3型。Kindlin-3在不同于talin-1的位点结合 β2-整合素胞质尾,但kindlin-3激活 β2-整合素的分子机制尚不清楚。在本研究中,我们测量了中性粒细胞和kindlin-3细胞在流动下滚动和停滞期间HL-60和 β2-整合素构象变化的时空动力学。使用高分辨率定量动态足迹显微镜和kindlin-3-fluorescent蛋白 (FP) 融合蛋白,我们发现在诱导H + β2-整合素构象之前,kindlin-3响应于interleukin-8 (IL-8) 被募集到质膜。活体成像显示,EGFP-kindlin-3-reconstituted,kindlin-3-knockout的嗜中性粒细胞在体内停止对cxcl1的反应。原代小鼠中性粒细胞中的EGFP-kindlin-3也在停滞前募集到质膜。在阻滞后,我们在膜近端kindlin-3 FP的大面积内发现了小的高亲和力 β2-整合素分子簇。在中性粒细胞样kindlin-3细胞中缺失HL-60或其pleckstrin同源性 (PH) 结构域完全消除H + β2-整合素诱导。IL-8还触发了在停滞之前将分离的kindlin-3 PH结构域募集到质膜。总之,我们表明kindlin-3 PH结构域对于募集到质膜是必需的,其中全长kindlin-3对于诱导高亲和力 β2-整联蛋白是不可或缺的。

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