Distinct Spatiotemporal Distribution of Bacterial Toxin-Produced Cellular cAMP Differentially Inhibits Opsonophagocytic Signaling

0519008 - MBÚ 2020 RIV CH eng J - Journal Article
Hasan, Shakir - Rahman, Waheed Ur - Šebo, Peter - Osička, Radim
Distinct Spatiotemporal Distribution of Bacterial Toxin-Produced Cellular cAMP Differentially Inhibits Opsonophagocytic Signaling.
Toxins. Roč. 11, č. 6 (2019), č. článku 362. ISSN 2072-6651. E-ISSN 2072-6651
R&D Projects: GA ČR(CZ) GA19-12695S; GA ČR(CZ) GA18-20621S; GA MŠMT(CZ) LM2015064
Research Infrastructure: EATRIS-CZ II - 90064
Institutional support: RVO:61388971
Keywords : 3',5 '-cyclic adenosine monophosphate (cAMP) * adenylate cyclase toxin * edema toxin
OECD category: Microbiology
Impact factor: 3.531, year: 2019
Method of publishing: Open access
https://www.mdpi.com/2072-6651/11/6/362

Myeloid phagocytes have evolved to rapidly recognize invading pathogens and clear them through opsonophagocytic killing. The adenylate cyclase toxin (CyaA) of Bordetella pertussis and the edema toxin (ET) of Bacillus anthracis are both calmodulin-activated toxins with adenylyl cyclase activity that invade host cells and massively increase the cellular concentrations of a key second messenger molecule, 3',5'-cyclic adenosine monophosphate (cAMP). However, the two toxins differ in the kinetics and mode of cell entry and generate different cAMP concentration gradients within the cell. While CyaA rapidly penetrates cells directly across their plasma membrane, the cellular entry of ET depends on receptor-mediated endocytosis and translocation of the enzymatic subunit across the endosomal membrane. We show that CyaA-generated membrane-proximal cAMP gradient strongly inhibits the activation and phosphorylation of Syk, Vav, and Pyk2, thus inhibiting opsonophagocytosis. By contrast, at similar overall cellular cAMP levels, the ET-generated perinuclear cAMP gradient poorly inhibits the activation and phosphorylation of these signaling proteins. Hence, differences in spatiotemporal distribution of cAMP produced by the two adenylyl cyclase toxins differentially affect the opsonophagocytic signaling in myeloid phagocytes.
Permanent Link: http://hdl.handle.net/11104/0304012