ADF/cofilin promotes invadopodial membrane recycling during cell invasion in vivo.
ADF/cofilin promotes invadopodial membrane recycling during cell invasion in vivo.
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DOI：
10.1083/jcb.201312098
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发表时间：
2014-03-31
期刊：
影响因子：
--
通讯作者：
Sherwood DR
中科院分区：
文献类型：
--
作者：
Hagedorn EJ;Kelley LC;Naegeli KM;Wang Z;Chi Q;Sherwood DR
ADF/cofilin 的局部 F-肌动蛋白分解可通过内溶酶体驱动侵入足膜回收，从而促进细胞通过基底膜进行有效的迁移。侵袭伪足是突出的、F-肌动蛋白驱动的膜结构，被认为在发育和肿瘤传播过程中介导基底膜迁移。由于难以在本地环境中检查这些动态结构，阻碍了对调节入侵伪足机制的理解。通过对秀丽隐杆线虫锚细胞 (AC) 入侵进行 RNAi 筛选和活细胞成像，我们发现 UNC-60A (ADF/cofilin) 是入侵伪足的重要调节因子。 UNC-60A 定位于 AC 侵袭伪足，其缺失导致 F-肌动蛋白动力学急剧减慢并且无法突破基底膜。光学突出显示 UNC-60A 分解侵袭伪足处的肌动蛋白丝。令人惊讶的是，unc-60a 的丢失导致入侵足膜和相关成分在内溶酶体室内的积累。光漂白实验表明，在正常侵袭过程中，侵袭足膜通过内溶酶体进行快速回收。总之，这些结果将侵袭伪足膜确定为一种特殊的隔室，其循环形成动态、功能性的侵袭伪足依赖于 ADF/cofilin 的局部 F-肌动蛋白分解。
Localized F-actin disassembly by ADF/cofilin drives invadopodial membrane recycling through endolysosomes, which promotes efficient cell transmigration through the basement membrane. Invadopodia are protrusive, F-actin–driven membrane structures that are thought to mediate basement membrane transmigration during development and tumor dissemination. An understanding of the mechanisms regulating invadopodia has been hindered by the difficulty of examining these dynamic structures in native environments. Using an RNAi screen and live-cell imaging of anchor cell (AC) invasion in Caenorhabditis elegans, we have identified UNC-60A (ADF/cofilin) as an essential regulator of invadopodia. UNC-60A localizes to AC invadopodia, and its loss resulted in a dramatic slowing of F-actin dynamics and an inability to breach basement membrane. Optical highlighting indicated that UNC-60A disassembles actin filaments at invadopodia. Surprisingly, loss of unc-60a led to the accumulation of invadopodial membrane and associated components within the endolysosomal compartment. Photobleaching experiments revealed that during normal invasion the invadopodial membrane undergoes rapid recycling through the endolysosome. Together, these results identify the invadopodial membrane as a specialized compartment whose recycling to form dynamic, functional invadopodia is dependent on localized F-actin disassembly by ADF/cofilin.
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