Bacillus cereus Certhrax ADP-ribosylates Vinculin to Disrupt Focal Adhesion Complexes and Cell Adhesion

Abstract

Background:The host substrate for Certhrax toxin is unknown. Results: Certhrax toxin ADP-ribosylates vinculin at Arg-433, which disrupts focal adhesion complexes and host cell adhesion. Conclusion: Certhrax toxin is the first bacterial toxin to add a post-translational modification to vinculin to disrupt the actin cytoskeleton. Significance: This explains how Certhrax toxin can contribute to evasion of the host innate immune system.

Assembly and Function of the Bacillus anthracis S-Layer

“…pBC210 also carries pag2 (60% identity with pag ) and lef 2 (36% identity with lef ) (Figure 1); the lef 2 product shows the presence of a putative PA binding domain; however, the metalloprotease domain of LF is replaced with an ADP-ribosyltransferase domain (41, 143). The lef 2 product, which has been designated Certhrax, is translocated by PA2 into host cells, modifies the host factor vinculin, and disrupts focal adhesion complexes (131, 143). These features of B. anthracis and B. cereus may account for the observed variation in disease severity and geographic spread associated with spores causing anthrax or anthrax-like disease.…”

Certhrax Is an Antivirulence Factor for the Anthrax-Like Organism Bacillus cereus Strain G9241

“…While the protein shares structural homology with other known ADPRTs, it appears to be unique to G9241 and, perhaps, B. cereus 03BB87, a strain that is genetically indistinguishable from G9241. Certhrax was shown to inactivate vinculin in vitro, a target that prior to the study by Simon and Barbieri had not been described for ADPRTs (5). These investigators theorized that Certhrax could contribute to bacterial spread within the host following infection with G9241 because the toxin, when transfected into cells, disrupts actin polymerization and subsequently changes cell morphology.…”

“…The second hypothesis was that the loss of the ADP-ribosylating activity of Certhrax was responsible for the virulence phenotype of the Δcer Δlef mutant strain of G9241. Vinculin has been identified as the target for Certhrax in HeLa cells (5). Vinculin is a critical protein in cell-cell and cell-matrix adhesion complexes, as it binds actin to promote its polymerization and recruits remodeling proteins to the complexes.…”

“…Moreover, the pBC210 plasmid carries two other loci for unique products of potential pathogenic significance for G9241. These are PA2, a homolog of PA (called PA1 in G9241) that shares 60% amino acid identity (2), and Certhrax, a novel ADPribosyltransferase toxin (ADPRT) that posttranslationally modifies and inactivates human vinculin (5).…”

Plasma membrane-associated superstructure: Have we overlooked a new type of organelle in eukaryotic cells?

“…Finally, pathogens can also affect cells and cause pathologies by targeting these plasma membrane-associated superstructures. For instance, some strains of the Bacillus cereus that cause anthrax-like diseases and death, encode the ADP-ribosyltransferase Certhrax that targets in focal adhesions the cytoskeletal protein vinculin (Simon and Barbieri, 2014). A variety of microorganisms, including Helicobacter pylori, that causes chronic inflammation of the gastric mucosa and have been associates to the development of gastric cancers, use CagA proteins or likewise proteins interfere with molecules in focal adhesions, tight junctions and adherens junctions (Amieva et al, 2003;Costa et al, 2013;Wessler and Backert, 2008;Zihni et al, 2014).…”