Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization
Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization
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DOI：
10.1038/ncb1541
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发表时间：
2007-03-01
影响因子：
21.3
通讯作者：
Yuan, Junying
中科院分区：
文献类型：
--
作者：
Li, Juying;Brieher, William M.;Yuan, Junying
细胞迁移、细胞因子成熟和细胞凋亡的协调调节在炎症反应中至关重要。半胱氨酸蛋白酶是一类半胱氨酸蛋白酶家族，已知其调节细胞因子成熟和凋亡。在这里，我们表明，caspase-11，哺乳动物促炎caspase，调节炎症过程中的细胞迁移。Caspase-11缺陷的淋巴细胞在体外和体内表现出细胞自主迁移缺陷。我们证明，caspase-11相互作用的物理和功能与肌动蛋白相互作用蛋白1（Aip 1），cofilin介导的肌动蛋白解聚的激活剂。caspase-11的caspase-募集结构域（CARD）与Aip 1的羧基末端WD 40推进器结构域相互作用以促进cofilin介导的肌动蛋白解聚。Aip 1或caspase-11缺陷的细胞表现出肌动蛋白动力学缺陷。使用体外肌动蛋白解聚试验，我们发现caspase-11和Aip 1协同工作，以促进cofilin介导的肌动蛋白解聚。这些数据表明，一种新的细胞自主半胱天冬酶介导的机制，调节肌动蛋白动力学和哺乳动物细胞迁移不同的受体介导的Rho-Rac-Cdc 42途径。
Coordinated regulation of cell migration, cytokine maturation and apoptosis is critical in inflammatory responses. Caspases, a family of cysteine proteases, are known to regulate cytokine maturation and apoptosis. Here, we show that caspase-11, a mammalian pro-inflammatory caspase, regulates cell migration during inflammation. Caspase-11-deficient lymphocytes exhibit a cell-autonomous migration defect in vitro and in vivo. We demonstrate that caspase-11 interacts physically and functionally with actin interacting protein 1 ( Aip1),an activator of cofilin-mediated actin depolymerization. The caspase-recruitment domain ( CARD) of caspase-11 interacts with the carboxy-terminal WD40 propeller domain of Aip1 to promote cofilin-mediated actin depolymerization. Cells with Aip1 or caspase-11 deficiency exhibit defects in actin dynamics. Using in vitro actin depolymerization assays, we found that caspase-11 and Aip1 work cooperatively to promote cofilin-mediated actin depolymerization. These data demonstrate a novel cell autonomous caspase-mediated mechanism that regulates actin dynamics and mammalian cell migration distinct from the receptor mediated Rho-Rac-Cdc42 pathway.