Histone Methyltransferase Ezh2 Controls Cell Adhesion and Migration through Direct Methylation of the Extra-Nuclear Protein-Talin

Previously, we suggested a cytosolic role for the histone-methyltransferase Ezh2 in regulating lymphocyte activation, but molecular mechanisms underpinning this extra-nuclear function remained unclear. Here we show that Ezh2 regulates integrin-signaling and adhesion dynamics of neutrophils and dendritic cells. Ezh2 deficiency impaired integrin-dependent transendothelial migration of innate leukocytes and restricted disease progression in an animal model of multiple sclerosis. Direct methylation of talin, a key regulatory molecule in cell migration, by Ezh2 disrupted talin binding to F-actin and thereby promoted adhesion structure turnover. This regulatory effect was abolished by targeted disruption of Ezh2 interactions with Vav1. Our studies reveal a novel extra-nuclear function for Ezh2 in regulating adhesion dynamics with implications for leukocyte migration, immune responses and potentially pathogenic processes. Control and Ezh2-deficient bone marrow derived immature and mature dendritic cells were analyzed in triplicates

既往我们曾提出，组蛋白甲基转移酶Ezh2（histone-methyltransferase Ezh2）具有胞质功能，可调控淋巴细胞活化，但支撑这一核外功能的分子机制此前尚不明确。本研究证实，Ezh2可调控中性粒细胞与树突状细胞的整合素信号通路及黏附动态。Ezh2缺陷会损伤先天白细胞依赖整合素的跨内皮迁移能力，并在多发性硬化症动物模型中限制疾病进展。Ezh2可直接甲基化细胞迁移关键调控分子踝蛋白（talin），该修饰会破坏踝蛋白与肌动蛋白丝（F-actin）的结合，进而促进黏附结构周转。通过靶向破坏Ezh2与Vav1蛋白的相互作用，这一调控效应会被完全消除。本研究揭示了Ezh2的新型核外功能，其可调控黏附动态，对白细胞迁移、免疫应答及潜在致病过程均具有调控意义。本研究对对照组与Ezh2缺陷型骨髓来源未成熟及成熟树突状细胞进行了三次重复实验分析。