Constitutively active ezrin increases membrane tension, slows migration, and impedes endothelial transmigration of lymphocytes in vivo in mice
Constitutively active ezrin increases membrane tension, slows migration, and impedes endothelial transmigration of lymphocytes in vivo in mice
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DOI：
10.1182/blood-2011-07-368860
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发表时间：
2012-01-12
期刊：
影响因子：
20.3
通讯作者：
Shaw, Stephen
中科院分区：
文献类型：
--
作者：
Liu, Yin;Belkina, Natalya V.;Shaw, Stephen
淋巴细胞中的ERM（ezrin，radixin moesin）蛋白将皮质肌动蛋白连接到质膜，这部分地由ERM蛋白磷酸化调节。为了评估ERM蛋白的磷酸化是否调节淋巴细胞迁移和膜张力，我们产生了转基因小鼠，其T淋巴细胞表达低水平的ezrin磷酸化模拟蛋白（T567 E）。在这些小鼠中，淋巴结中的T细胞数量减少了27%。淋巴结中淋巴细胞的体外和体内迁移率降低18%~ 47%。淋巴细胞膜张力增加71%。其他可能的潜在机制的调查显示，受损的趋化因子诱导的形状变化/片状延伸和整合素介导的粘附增加。值得注意的是，淋巴细胞归巢到淋巴结减少了30%。与大多数描述的归巢缺陷不同，没有受损的滚动或粘附淋巴结血管内皮，而是减少了穿过内皮的迁移。此外，输出淋巴中转基因T细胞的数量减少表明有缺陷的出口。这些研究证实了ERM去磷酸化在调节淋巴细胞迁移和转移中的关键作用。特别值得注意的是，他们将磷酸化-ERM确定为第一个描述的淋巴细胞膜张力调节剂，其增加可能导致在ezrin T567 E转基因小鼠中观察到的多种缺陷。（血。2012;119（2）：445-453）
ERM (ezrin, radixin moesin) proteins in lymphocytes link cortical actin to plasma membrane, which is regulated in part by ERM protein phosphorylation. To assess whether phosphorylation of ERM proteins regulates lymphocyte migration and membrane tension, we generated transgenic mice whose T-lymphocytes express low levels of ezrin phosphomimetic protein (T567E). In these mice, T-cell number in lymph nodes was reduced by 27%. Lymphocyte migration rate in vitro and in vivo in lymph nodes decreased by 18% to 47%. Lymphocyte membrane tension increased by 71%. Investigations of other possible underlying mechanisms revealed impaired chemokine-induced shape change/lamellipod extension and increased integrin-mediated adhesion. Notably, lymphocyte homing to lymph nodes was decreased by 30%. Unlike most described homing defects, there was not impaired rolling or sticking to lymph node vascular endothelium but rather decreased migration across that endothelium. Moreover, decreased numbers of transgenic T cells in efferent lymph suggested defective egress. These studies confirm the critical role of ERM dephosphorylation in regulating lymphocyte migration and transmigration. Of particular note, they identify phospho-ERM as the first described regulator of lymphocyte membrane tension, whose increase probably contributes to the multiple defects observed in the ezrin T567E transgenic mice. (Blood. 2012;119(2):445-453)