Adenylate cyclase toxin (CyaA or ACT) is a key virulence factor of pathogenic Bordetellae. It penetrates phagocytes expressing the alpha(M)beta(2) integrin (CD11b/CD18, Mac-1 or CR3) and paralyzes their bactericidal capacities by uncontrolled conversion of ATP into a key signaling molecule, cAMP. Using pull-down activity assays and transfections with mutant Rho family GTPases, we show that cAMP signaling of CyaA causes transient and selective inactivation of RhoA in mouse macrophages in the absence of detectable activation of Rac1, Rac2, or RhoG. This CyaA/cAMP-induced drop of RhoA activity yielded dephosphorylation of the actin filament severing protein cofilin and massive actin cytoskeleton rearrangements, which were paralleled by rapidly manifested macrophage ruffling and a rapid and unexpected loss of macropinocytic fluid phase uptake. As shown in this study for the first time, CyaA/cAMP signaling further caused a rapid and near-complete block of complement-mediated phagocytosis. Induction of unproductive membrane ruffling, hence, represents a novel sophisticated mechanism of down-modulation of bactericidal activities of macrophages and a new paradigm for action of bacterial toxins that hijack host cell signaling by manipulating cellular cAMP levels.
- MeSH
- adenylátcyklasový toxin imunologie metabolismus MeSH
- AMP cyklický imunologie MeSH
- antigeny CD11b genetika imunologie MeSH
- antigeny CD18 genetika imunologie MeSH
- Bordetella pertussis enzymologie imunologie MeSH
- buněčná membrána imunologie metabolismus MeSH
- buněčné linie MeSH
- faktory depolymerizující aktin imunologie metabolismus MeSH
- financování organizované MeSH
- GTP-fosfohydrolasy imunologie metabolismus MeSH
- makrofágový antigen 1 imunologie metabolismus MeSH
- makrofágy imunologie metabolismus MeSH
- mikrofilamenta imunologie metabolismus MeSH
- myši MeSH
- neuropeptidy imunologie metabolismus MeSH
- pertuse enzymologie imunologie MeSH
- rac proteiny vázající GTP imunologie metabolismus MeSH
- rho proteiny vázající GTP imunologie metabolismus MeSH
- signální transdukce imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
