Abrami Laurence, Kunz Béatrice, Deuquet Julie, Bafico Anna, Davidson Gary, van der Goot F Gisou
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Station 15, CH 1015 Lausanne, Switzerland.
Cell Microbiol. 2008 Dec;10(12):2509-19. doi: 10.1111/j.1462-5822.2008.01226.x. Epub 2008 Aug 20.
To exert its activity, anthrax toxin must be endocytosed and its enzymatic toxic subunits delivered to the cytoplasm. It has been proposed that, in addition to the anthrax toxin receptors (ATRs), lipoprotein-receptor-related protein 6 (LRP6), known for its role in Wnt signalling, is also required for toxin endocytosis. These findings have however been challenged. We show that LRP6 can indeed form a complex with ATRs, and that this interaction plays a role both in Wnt signalling and in anthrax toxin endocytosis. We found that ATRs control the levels of LRP6 in cells, and thus the Wnt signalling capacity. RNAi against ATRs indeed led to a drastic decrease in LRP6 levels and a subsequent drop in Wnt signalling. Conversely, LRP6 plays a role in anthrax toxin endocytosis, but is not essential. We indeed found that toxin binding triggered tyrosine phosphorylation of LRP6, induced its redistribution into detergent-resistant domains, and its subsequent endocytosis. RNAis against LRP6 strongly delayed toxin endocytosis. As the physiological role of ATRs is probably to interact with the extracellular matrix, our findings raise the interesting possibility that, through the ATR-LRP6 interaction, adhesion to the extracellular matrix could locally control Wnt signalling.
炭疽毒素要发挥其活性，必须被内吞，其酶毒性亚基被递送至细胞质。有人提出，除了炭疽毒素受体（ATR）外，脂蛋白受体相关蛋白6（LRP6），因其在Wnt信号传导中的作用而闻名，对于毒素内吞作用也是必需的。然而，这些发现受到了质疑。我们表明，LRP6确实可以与ATR形成复合物，并且这种相互作用在Wnt信号传导和炭疽毒素内吞作用中都发挥作用。我们发现，ATR控制细胞中LRP6的水平，从而控制Wnt信号传导能力。针对ATR的RNA干扰确实导致LRP6水平急剧下降，随后Wnt信号传导减弱。相反，LRP6在炭疽毒素内吞作用中发挥作用，但不是必需的。我们确实发现，毒素结合引发了LRP6的酪氨酸磷酸化，诱导其重新分布到抗去污剂结构域，并随后被内吞。针对LRP6的RNA干扰强烈延迟了毒素内吞作用。由于ATR的生理作用可能是与细胞外基质相互作用，我们的发现提出了一个有趣的可能性，即通过ATR-LRP6相互作用，与细胞外基质的粘附可能局部控制Wnt信号传导。
