An Updated Model of Anthrax Toxin Function

The bacterium Bacillus anthracis produces a toxin containing three components: two that are enzymatically active (lethal factor/LF and edema factor/EF) and one that mediates target cell entry (protective antigen/PA). LF is a protease that inactivates MAPK proteins, while EF is an adenylate cyclase.1 Both LF and EF induce widespread disruption of intracellular signaling cascades. On the target cell, CMG-2 and TEM8/ATR bind PA and confer sensitivity to anthrax toxin. Recent investigations into the interaction of PA with target cells have added to the understanding of anthrax pathogenicity.2

CMG-2 is a widely expressed transmembrane protein that mediates cellular adhesion to collagen type IV and laminin.3 TEM8 was identified as a protein that is upregulated on angiogenic endothelial cells such as those lining tumor vasculature.4,5 It couples extracellular matrix collagens I and VI to the actin cytoskeleton and mediates endothelial cell spreading.4,6 Both CMG-2 and TEM8 have a single extracellular VWF-A domain. LRP-6 is a transmembrane protein that functions as a Wnt co-receptor by associating with Frizzled and Dickkopf proteins.7,8

Figure 1
Figure 1. PA83 binds to the receptor complex and is cleaved by a furin-like protease to release a 20 kDa fragment. A large heptameric complex forms, binds LF and/or EF, and moves to lipid rafts. Internalization is triggered by ubiquitination of CMG-2 and TEM8. PA63 subunits detach from the complex in the acidic environment of the endosome and form a pore that enables LF and EF translocation to the cytoplasm.

Several recent studies have clarified the working model of anthrax toxin cellular entry (Figure 1). The process begins with binding of the 83 kDa PA (PA83) to the VWF domain of either CMG-2 or TEM8.9,10 The extracellular domains of these receptors interact with the extracellular domain of LRP-6, an association that is enhanced by the binding of PA83.2 LRP6 is required for the internalization and lethality of anthrax toxin.2 A furin-like protease then removes a 20 kDa fragment from PA83.1 The remaining PA63 fragment, in complex with the receptor and LRP-6, assembles into a ring-like heptamer on the plasma membrane and binds LF or EF toxin components.2 CMG-2 and TEM8 are palmitoylated, which prevents their localization into lipid rafts.11 Subsequent to PA binding, however, the receptors move into lipid rafts where they become ubiquitinated by the ligase Cbl, resulting in internalization of the complex.11 Endosomal acidification triggers release of PA63 from the receptors and formation of a PA63 pore through which LF and EF enter the cytoplasm to poison the cell.1 PA63 detachment from CMG-2 occurs at a lower pH than from TEM8, corresponding to distinct stages of the endocytic pathway.12 Alternately spliced soluble forms of both CMG-2 and TEM8 may function as decoy receptors that inhibit anthrax toxicity.9,10

These studies of anthrax toxin have identified novel functions for CMG-2 and TEM8 and elucidated additional co-receptor partners for LRP6. CMG-2 and TEM8, previously described as adhesion proteins with extracellular matrix ligands, have now been shown to internalize in the presence of anthrax toxin. LRP6, well studied as a co-receptor for Wnt and related proteins, now has an expanded repertoire. Further research may shed additional light onto the roles of these proteins in the biology of Bacillus anthracis.


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