The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin.
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.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Wensheng
W
Wei
Quan
Q
Lu
G Jilani
GJ
Chaudry
Stephen H
SH
Leppla
Stanley N
SN
Cohen
D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D001427:Bacterial Toxins / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D018000:Receptors, Peptide; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
C473287:ANTXR1 protein, human; C447150:ANTXR2 protein, human; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D018000:Receptors, Peptide; D051153:Wnt Proteins; C030325:anthrax toxin