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

Institute of Microbiology of the CAS, v. v. i., Videnska 1083, 142 20 Prague, Czech Republic
*
Author to whom correspondence should be addressed.
Both authors contributed equally to this work.
Current address: Laboratory of Immunophysiology, GIGA Institute, Liege University, 4000 Liege, Belgium.
Toxins 2019, 11(6), 362; https://doi.org/10.3390/toxins11060362
Received: 10 May 2019 / Revised: 12 June 2019 / Accepted: 18 June 2019 / Published: 20 June 2019
(This article belongs to the Special Issue RTX Toxins)
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Abstract

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. View Full-Text
Keywords: 3′,5′-cyclic adenosine monophosphate (cAMP); adenylate cyclase toxin; edema toxin; opsonophagocytosis; phagocytes; Syk; Vav; Pyk2; signaling pathway 3′,5′-cyclic adenosine monophosphate (cAMP); adenylate cyclase toxin; edema toxin; opsonophagocytosis; phagocytes; Syk; Vav; Pyk2; signaling pathway
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Hasan, S.; Rahman, W.U.; Sebo, P.; Osicka, R. Distinct Spatiotemporal Distribution of Bacterial Toxin-Produced Cellular cAMP Differentially Inhibits Opsonophagocytic Signaling. Toxins 2019, 11, 362.

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