FAN在磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P）限制的质膜定位参与肿瘤坏死因子（TNF）诱导的肌动蛋白重组。
PtdIns(4,5)P-restricted plasma membrane localization of FAN is involved in TNF-induced actin reorganization.
作者信息
Haubert Dirk, Gharib Nina, Rivero Francisco, Wiegmann Katja, Hösel Marianna, Krönke Martin, Kashkar Hamid
机构信息
Institute for Medical Microbiology, Immunology and Hygiene, Medical Faculty, University of Cologne, Cologne, Germany.
出版信息
EMBO J. 2007 Jul 25;26(14):3308-21. doi: 10.1038/sj.emboj.7601778. Epub 2007 Jun 28.
The WD-repeat protein factor associated with nSMase activity (FAN) is a member of the family of TNF receptor adaptor proteins that are coupled to specific signaling cascades. However, the precise functional involvement of FAN in specific cellular TNF responses remain unclear. Here, we report the involvement of FAN in TNF-induced actin reorganization and filopodia formation mediated by activation of Cdc42. The pleckstrin-homology (PH) domain of FAN specifically binds to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P), which targets FAN to the plasma membrane. Site-specific mutagenesis revealed that the ability of FAN to mediate filopodia formation was blunted either by the destruction of the PtdIns(4,5)P binding motif, or by the disruption of intramolecular interactions between the PH domain and the adjacent beige and Chediak-Higashi (BEACH) domain. Furthermore, FAN was shown to interact with the actin cytoskeleton in TNF-stimulated cells via direct filamentous actin (F-actin) binding. The results of this study suggest that PH-mediated plasma membrane targeting of FAN is critically involved in TNF-induced Cdc42 activation and cytoskeleton reorganization.
与神经鞘磷脂酶（nSMase）活性相关的WD重复蛋白因子（FAN）是与特定信号级联反应偶联的肿瘤坏死因子受体（TNF）衔接蛋白家族的成员。然而，FAN在特定细胞TNF反应中的精确功能仍不清楚。在此，我们报道了FAN参与由Cdc42激活介导的TNF诱导的肌动蛋白重组和丝状伪足形成。FAN的普列克底物蛋白同源（PH）结构域特异性结合磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P），将FAN靶向到质膜。位点特异性诱变显示，破坏PtdIns(4,5)P结合基序或破坏PH结构域与相邻的米色和切-东综合征（BEACH）结构域之间的分子内相互作用，均会削弱FAN介导丝状伪足形成的能力。此外，在TNF刺激的细胞中，FAN通过直接结合丝状肌动蛋白（F-肌动蛋白）与肌动蛋白细胞骨架相互作用。本研究结果表明，PH介导的FAN质膜靶向在TNF诱导的Cdc42激活和细胞骨架重组中起关键作用。
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