N-WASP inhibitor wiskostatin nonselectively perturbs membrane transport by decreasing cellular ATP levels
N-WASP inhibitor wiskostatin nonselectively perturbs membrane transport by decreasing cellular ATP levels
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DOI：
10.1152/ajpcell.00426.2006
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发表时间：
2007-04-01
影响因子：
5.5
通讯作者：
Weisz, Ora A.
中科院分区：
文献类型：
--
作者：
Guerriero, Christopher J.;Weisz, Ora A.
Wiskott-Aldrich综合征蛋白（WASP）和WAVE刺激肌动蛋白相关蛋白（阿普）2/3介导的肌动蛋白聚合，导致多种下游效应，包括细胞表面突起的形成和重塑、细胞迁移的调节以及细胞器和病原体的胞浆内推进.个别Arp 2/3活化剂的选择性抑制剂将使得能够更精确地剖析WASP和WAVE依赖性细胞途径，并且是病毒发病机制的潜在治疗靶标。Wiskostatin是近年来发现的一种化学抑制剂，能选择性地抑制神经元WASP（N-WASP）介导的肌动蛋白聚合.最近越来越多的研究已经在体内利用这种药物来揭示N-WASP的新细胞功能;然而，未仔细探索wiskostatin在完整细胞中的选择性。在我们对这种药物的研究中，我们观察到对N-WASP依赖性膜运输步骤的快速和剂量依赖性抑制.然而，另外，我们发现添加wiskostatin抑制了许多其他被认为不是N-WASP依赖性的细胞功能。进一步的研究表明，威舒他汀治疗会导致细胞ATP水平迅速、深刻且不可逆转地下降，这与其对细胞功能的整体影响一致。我们的数据警告不要使用这种药物作为体内N-WASP依赖性肌动蛋白动力学的选择性扰动剂。
Wiskott- Aldrich syndrome protein ( WASP) and WAVE stimulate actin- related protein ( Arp)2/3-mediated actin polymerization, leading to diverse downstream effects, including the formation and remodeling of cell surface protrusions, modulation of cell migration, and intracytoplasmic propulsion of organelles and pathogens. Selective inhibitors of individual Arp2/3 activators would enable more exact dissection of WASP- and WAVE- dependent cellular pathways and are potential therapeutic targets for viral pathogenesis. Wiskostatin is a recently described chemical inhibitor that selectively inhibits neuronal WASP ( N- WASP)- mediated actin polymerization in vitro. A growing number of recent studies have utilized this drug in vivo to uncover novel cellular functions for N- WASP; however, the selectivity of wiskostatin in intact cells has not been carefully explored. In our studies with this drug, we observed rapid and dose- dependent inhibition of N- WASP- dependent membrane trafficking steps. Additionally, however, we found that addition of wiskostatin inhibited numerous other cellular functions that are not believed to be N- WASP dependent. Further studies revealed that wiskostatin treatment caused a rapid, profound, and irreversible decrease in cellular ATP levels, consistent with its global effects on cell function. Our data caution against the use of this drug as a selective perturbant of N- WASP-dependent actin dynamics in vivo.