Wei Wensheng, Lu Quan, Chaudry G Jilani, Leppla Stephen H, Cohen Stanley N
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2006 Mar 24;124(6):1141-54. doi: 10.1016/j.cell.2005.12.045.
Toxins produced by Bacillus anthracis and other microbial pathogens require functions of host cell genes to yield toxic effects. Here we show that low density lipoprotein receptor-related protein 6 (LRP6), previously known to be a coreceptor for the Wnt signaling pathway, is required for anthrax toxin lethality in mammalian cells. Downregulation of LRP6 or coexpression of a truncated LRP6 dominant-negative peptide inhibited cellular uptake of complexes containing the protective antigen (PA) carrier of anthrax toxin moieties and protected targeted cells from death, as did antibodies against epitopes in the LRP6 extracellular domain. Fluorescence microscopy and biochemical analyses showed that LRP6 enables toxin internalization by interacting at the cell surface with PA receptors TEM8/ATR and/or CMG2 to form a multicomponent complex that enters cells upon PA binding. Our results, which reveal a previously unsuspected biological role for LRP6, identify LRP6 as a potential target for countermeasures against anthrax toxin lethality.
炭疽芽孢杆菌及其他微生物病原体产生的毒素需要宿主细胞基因的功能才能产生毒性作用。我们在此表明，低密度脂蛋白受体相关蛋白6（LRP6）——此前已知其为Wnt信号通路的共受体——是炭疽毒素在哺乳动物细胞中产生致死作用所必需的。LRP6的下调或截短的LRP6显性负性肽的共表达抑制了含有炭疽毒素部分的保护性抗原（PA）载体的复合物的细胞摄取，并保护靶细胞免于死亡，针对LRP6细胞外结构域表位的抗体也有同样效果。荧光显微镜检查和生化分析表明，LRP6通过在细胞表面与PA受体TEM8/ATR和/或CMG2相互作用，使毒素内化，形成一种多组分复合物，该复合物在PA结合后进入细胞。我们的结果揭示了LRP6此前未被怀疑的生物学作用，确定LRP6是对抗炭疽毒素致死作用的潜在对策靶点。
