The cortactin-binding domain of WIP is essential for podosome formation and extracellular matrix degradation by murine dendritic cells
The cortactin-binding domain of WIP is essential for podosome formation and extracellular matrix degradation by murine dendritic cells
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DOI：
10.1016/j.ejcb.2010.09.001
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发表时间：
2011-02-01
影响因子：
6.6
通讯作者：
Anton, Ines M.
中科院分区：
文献类型：
--
作者：
Banon-Rodriguez, Inmaculada;Monypenny, James;Anton, Ines M.
在未成熟的树突状细胞（dc）中，足质体形成并在迁移细胞的前沿后面翻转。Arp2/3复合物激活因子Wiskott-Aldrich综合征蛋白（WASP）与WASP相互作用蛋白（WIP）一起定位于形成足小体的肌动蛋白核心。另一种较弱的Arp2/3激活剂，接触蛋白，也在足质体中发现，它被认为参与基质金属蛋白酶（MMP）的分泌。我们之前已经证明WIP-/- dc不能产生足质体。WIP与接触蛋白结合，在本报告中，我们讨论了WIP是否调节接触蛋白介导的MMP活性。使用来自脾小鼠前体的dc，我们发现野生型细胞能够将MMPs定位于基质降解发生的足质体。相比之下，WIP-/- dc仍然能够合成MMPs，但不降解细胞外基质。用表达WIP的慢病毒感染WIP KO dc恢复了podosome的形成及其降解细胞外基质的能力，这表明WIP诱导的podosome是功能性MMP定位的重点。当WIP KO dc被缺乏接触蛋白结合结构域的突变型WIP （WIP Delta 110-170）感染时，dc只能精心制作无组织的足质体，无法支持mmp介导的基质降解。综上所述，这些结果表明WIP不仅在wasp介导的肌动蛋白聚合和足质体形成中起作用，而且在MMPs介导的接触蛋白介导的细胞外基质降解中也起作用。(C) 2010 Elsevier GmbH版权所有。
In immature dendritic cells (DCs) podosomes form and turn over behind the leading edge of migrating cells. The Arp2/3 complex activator Wiskott-Aldrich Syndrome Protein (WASP) localises to the actin core of forming podosomes together with WASP-Interacting Protein (WIP). A second weaker Arp2/3 activator, cortactin, is also found at podosomes where it has been proposed to participate in matrix metalloproteinase (MMP) secretion. We have previously shown that WIP-/- DCs are unable to make podosomes. WIP binds to cortactin and in this report we address whether WIP regulates cortactin-mediated MMP activity. Using DCs derived from splenic murine precursors, we found that wild-type cells were able to localise MMPs at podosomes where matrix degradation takes place. In contrast, WIP-/- DCs remain able to synthesise MMPs but do not degrade the extracellular matrix. Infection of WIP KO DCs with lentivirus expressing WIP restored both podosome formation and their ability to degrade the extracellular matrix, implicating WIP-induced podosomes as foci of functional MMP location. When WIP KO DCs were infected with a mutant form of WIP lacking the cortactin-binding domain (WIP Delta 110-170) DCs were only able to elaborate disorganised podosomes that were unable to support MMP-mediated matrix degradation. Taken together, these results suggest a role for WIP not only in WASP-mediated actin polymerisation and podosome formation, but also in cortactin-mediated extracellular matrix degradation by MMPs. (C) 2010 Elsevier GmbH. All rights reserved.