Inside Out Integrin Activation Mediated by PIEZO1 Signaling in Erythroblasts
Inside Out Integrin Activation Mediated by PIEZO1 Signaling in Erythroblasts
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PIEZO 1信号通路介导的成红细胞整合素由内而外激活
DOI：
10.3389/fphys.2020.00958
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发表时间：
2020-07-31
影响因子：
4
通讯作者：
van den Akker, Emile
中科院分区：
文献类型：
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作者：
Aglialoro, Francesca;Hofsink, Naomi;van den Akker, Emile
非选择性机械敏感离子通道PIEZO 1控制红细胞体积动态平衡。PIEZO 1基因中不同的错义功能获得性突变已被鉴定为导致遗传性干细胞症（HX），一种罕见的常染色体显性溶血性贫血。PIEZO 1表达不限于红细胞，并且在红系前体中表达水平显著更高，暗示在红细胞生成中的作用。在红细胞生成过程中，成红细胞、中央巨噬细胞和成红细胞岛内的细胞外基质之间的相互作用是重要的。存在于成红细胞上的整合素α 4 β 1和α 5 β 1促进成红细胞岛中的这种相互作用。在这里，我们发现，使用Yoda1的PIEZO 1的化学活化导致在流动条件下与VCAM 1和纤连蛋白的粘附增加。整合素α 4、α 5和β 1阻断抗体阻止了这种PIEZO 1诱导的粘附，表明成红细胞上整合素的由内而外活化。通过使用特异性抑制剂阻断Ca 2+依赖性钙蛋白酶和PKC途径也阻断了红系细胞对VCAM 1和纤连蛋白的粘附增加。Talin的切割被观察到作为Calpain和PKC活性的结果。总之，PIEZO 1激活导致由内而外的整合素激活，通过PKC和钙蛋白酶的钙依赖性激活促进。这些数据介绍了红细胞生成过程中Ca2+信号传导的新概念，以及健康和遗传性干细胞症等疾病中成红细胞岛稳态的衍生物。
The non-selective mechanosensitive ion channel PIEZO1 controls erythrocyte volume homeostasis. Different missense gain-of-function mutations in PIEZO1 gene have been identified that cause Hereditary Xerocytosis (HX), a rare autosomal dominant haemolytic anemia. PIEZO1 expression is not limited to erythrocytes and expression levels are significantly higher in erythroid precursors, hinting to a role in erythropoiesis. During erythropoiesis, interactions between erythroblasts, central macrophages, and extracellular matrix within erythroblastic islands are important. Integrin alpha 4 beta 1 and alpha 5 beta 1 present on erythroblasts facilitate such interactions in erythroblastic islands. Here we found that chemical activation of PIEZO1 using Yoda1 leads to increased adhesion to VCAM1 and fibronectin in flowing conditions. Integrin alpha 4, alpha 5, and beta 1 blocking antibodies prevented this PIEZO1-induced adhesion suggesting inside-out activation of integrin on erythroblasts. Blocking the Ca2+ dependent Calpain and PKC pathways by using specific inhibitors also blocked increased erythroid adhesion to VCAM1 and fibronectins. Cleavage of Talin was observed as a result of Calpain and PKC activity. In conclusion, PIEZO1 activation results in inside-out integrin activation, facilitated by calcium-dependent activation of PKC and Calpain. The data introduces novel concepts in Ca2+ signaling during erythropoiesis with ramification on erythroblastic island homeostasis in health and disease like Hereditary Xerocytosis.