BCL6 suppresses RhoA activity to alter macrophage morphology and motility
BCL6 suppresses RhoA activity to alter macrophage morphology and motility
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DOI：
10.1242/jcs.02314
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发表时间：
2005-05-01
影响因子：
4
通讯作者：
Ye, BH
中科院分区：
文献类型：
--
作者：
Pixley, FJ;Xiong, Y;Ye, BH
BCL6是一种有效的转录抑制因子，在生发中心形成、T辅助细胞分化和淋巴瘤发生中发挥重要作用，并调节巨噬细胞中几种趋化因子基因的表达。在对其在巨噬细胞中的作用的进一步研究中，我们发现BCL6在原代骨髓源性巨噬细胞中的失活导致极化、运动和细胞扩散减少，并伴随着外周局灶复合物、锚定的f -肌动蛋白束和皮质f -肌动蛋白密度的增加。这些变化与RhoA的过度激活有关。C3转移酶对RhoA活性的抑制恢复了粘附结构表型，而Rho激酶抑制剂不影响粘附结构表型，这表明Rho的其他下游效应物维持了这种Bcl6（-/-）表型。bcl6缺陷巨噬细胞中RhoA的过度激活与p120RasGAP （RASA1）介导的p190RhoGAP （GRLF1）向质膜上活性RhoA的易位减少以及CSF1R细胞表面表达减少有关，据报道，CSF1R可将RasGAP招募到质膜上。重组BCL6在BCL6（-/-）巨噬细胞中的表达导致形态表型完全逆转，细胞表面CSF1R表达显著增加，而过表达CSF1R则纠正了极化和粘附结构缺陷。这些结果表明，BCL6主要通过上调表面CSF1R表达来抑制RhoA活性，从而调节细胞骨架和粘附结构，增加巨噬细胞的运动能力。
BCL6 is a potent transcriptional repressor that plays important roles in germinal center formation, T helper cell differentiation and lymphomagenesis and regulates expression of several chemokine genes in macrophages. In a further investigation of its role in macrophages, we show that BCL6 inactivation in primary bone marrow-derived macrophages leads to decreased polarization, motility and cell spreading accompanied by an increase in peripheral focal complexes, anchored F-actin bundles and cortical F-actin density. These changes were associated with excess RhoA activation. C3 transferase inhibition of RhoA activity reverted the adhesion structure phenotype, which was not affected by Rho kinase inhibitors, suggesting that other downstream effectors of Rho maintain this Bcl6(-/-) phenotype. Excess RhoA activation in BCL6-deficient macrophages is associated with a decrease in the p120RasGAP (RASA1)-mediated translocation of p190RhoGAP (GRLF1) to active RhoA at the plasma membrane and a reduction in cell surface expression of the CSF1R that has been reported to recruit RasGAP to the plasma membrane. Reconstitution of BCL6 expression in Bcl6(-/-) macrophages results in complete reversion of the morphological phenotype and a significant increase in cell surface CSF1R expression whereas overexpression of the CSF1R corrects the polarization and adhesion structure defects. These results demonstrate that BCL6 suppresses RhoA activity, largely through upregulation of surface CSF1R expression, to modulate cytoskeletal and adhesion structures and increase the motility of macrophages.