Centre National de la Recherche Scientifique, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
Blood. 2013 Jul 25;122(4):533-41. doi: 10.1182/blood-2012-11-466649. Epub 2013 Apr 30.
The actin-binding protein filamins (FLNs) are major organizers of the actin cytoskeleton. They control the elasticity and stiffness of the actin network and provide connections with the extracellular microenvironment by anchoring transmembrane receptors to the actin filaments. Although numerous studies have revealed the importance of FLN levels, relatively little is known about the regulation of its stability in physiological relevant settings. Here, we show that the ASB2α cullin 5-ring E3 ubiquitin ligase is highly expressed in immature dendritic cells (DCs) and is down-regulated after DC maturation. We further demonstrate that FLNs are substrates of ASB2α in immature DCs and therefore are not stably expressed in these cells, whereas they exhibit high levels of expression in mature DCs. Using ASB2 conditional knockout mice, we show that ASB2α is a critical regulator of cell spreading and podosome rosette formation in immature DCs. Furthermore, we show that ASB2(-/-) immature DCs exhibit reduced matrix-degrading function leading to defective migration. Altogether, our results point to ASB2α and FLNs as newcomers in DC biology.
肌动蛋白结合蛋白细丝蛋白（FLNs）是肌动蛋白细胞骨架的主要组织者。它们通过将跨膜受体锚定在肌动蛋白丝上来控制肌动蛋白网络的弹性和刚性，并与细胞外微环境建立连接。尽管许多研究已经揭示了 FLN 水平的重要性，但对于其在生理相关环境中的稳定性调节相对知之甚少。在这里，我们表明 ASB2α 环泛素连接酶是幼稚树突状细胞（DCs）中高度表达的，并在 DC 成熟后下调。我们进一步证明 FLNs 是 ASB2α 在幼稚 DCs 中的底物，因此在这些细胞中不稳定表达，而在成熟 DCs 中表达水平较高。使用 ASB2 条件性敲除小鼠，我们表明 ASB2α 是幼稚 DCs 中细胞铺展和足突玫瑰花结形成的关键调节剂。此外，我们表明 ASB2(-/-) 幼稚 DCs 表现出降低的基质降解功能，导致迁移缺陷。总之，我们的研究结果表明 ASB2α 和 FLNs 是 DC 生物学中的新成员。
