Boyer Laurent, Travaglione Sara, Falzano Loredana, Gauthier Nils C, Popoff Michel R, Lemichez Emmanuel, Fiorentini Carla, Fabbri Alessia
Institut National de la Santé et de la Recherche Médicale U452, IFR50, Faculté de Médecine, 06107 Nice, France.
Mol Biol Cell. 2004 Mar;15(3):1124-33. doi: 10.1091/mbc.e03-05-0301. Epub 2003 Dec 10.
Nuclear factor-kappaB (NF-kappaB) is a ubiquitously expressed transcription factor that plays a central role in directing a vast range of cellular functions. Its activation is controlled by the Rac GTPase and relies on the coordinated cooperation of the E3-ligase complex SCF(betaTrCP), composed by Skp-1/Cullin-1, Rbx/Roc1, and the beta-TrCP proteins. Recently, Cullin-1 has been reported to form a complex with the activated Rac GTPase. Here, we show that the specific activation of the Rac GTPase, besides directing its own positioning, induces the relocalization of the SCF component Cullin-1 to the ruffling membranes. This occurred only if the ruffles were stimulated by the Rac GTPase and was accompanied by the repositioning to the same intracellular compartment of the SCF protein Skp-1 and the ubiquitin-like molecule Nedd-8. The SCF substrate IkBalpha was also directed to the ruffling membranes in a Rac-dependent way. The novelty of these findings is in respect to the demonstration that the correct positioning at the ruffling membranes is crucial for the subsequent series of events that leads to IkBalpha proteasomal degradation and the resultant activation of NF-kappaB. Consequently, this points to the role of Rac as a docking molecule in NF-kappaB activation.
核因子-κB（NF-κB）是一种广泛表达的转录因子，在指导多种细胞功能中发挥核心作用。其激活受Rac GTP酶控制，并依赖于由Skp-1/Cullin-1、Rbx/Roc1和β-TrCP蛋白组成的E3连接酶复合物SCF（βTrCP）的协同作用。最近，有报道称Cullin-1与激活的Rac GTP酶形成复合物。在此，我们表明，Rac GTP酶的特异性激活除了指导其自身定位外，还诱导SCF成分Cullin-1重新定位到褶皱膜。只有当褶皱受到Rac GTP酶刺激时才会发生这种情况，同时伴随着SCF蛋白Skp-1和类泛素分子Nedd-8重新定位到相同的细胞内区室。SCF底物IkBα也以Rac依赖的方式被导向褶皱膜。这些发现的新颖之处在于证明了在褶皱膜上的正确定位对于导致IkBα蛋白酶体降解及随后NF-κB激活的一系列事件至关重要。因此，这表明Rac在NF-κB激活中作为对接分子的作用。
