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cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity

SYSNO ASEP	0473551
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity
Author(s)	Černý, Ondřej (MBU-M) Anderson, K.E. (GB) Stephens, L.R. (GB) Hawkins, P.T. (GB) Šebo, Peter (MBU-M)_{RID, ORCID}
Source Title	Journal of Immunology. - : American Association of Immunologists - ISSN 0022-1767 Roč. 198, č. 3 (2017), s. 1285-1296
Number of pages	12 s.
Language	eng - English
Country	US - United States
Keywords	BORDETELLA-PERTUSSIS ; NADPH OXIDASE ; CYCLIC-AMP
Subject RIV	EE - Microbiology, Virology
OECD category	Microbiology
R&D Projects	GA13-14547S GA ČR - Czech Science Foundation (CSF)
	LM2015064 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	MBU-M - RVO:61388971
UT WOS	000392412700031
EID SCOPUS	85014714905
DOI	10.4049/jimmunol.1601309
Annotation	The adenylate cyclase toxin-hemolysin (CyaA) plays a key role in immune evasion and virulence of the whooping cough agent Bordetella pertussis. CyaA penetrates the complement receptor 3 expressing phagocytes and ablates their bactericidal capacities by catalyzing unregulated conversion of cytosolic ATP to the key second messenger molecule cAMP. We show that signaling of CyaA-generated cAMP blocks the oxidative burst capacity of neutrophils by two converging mechanisms. One involves cAMP/ protein kinase A mediated activation of the Src homology region 2 domain containing phosphatase-1 (SHP-1) and limits the activation of MAPK ERK and p38 that are required for assembly of the NADPH oxidase complex. In parallel, activation of the exchange protein directly activated by cAMP (Epac) provokes inhibition of the phospholipase C by an as yet unknown mechanism. Indeed, selective activation of Epac by the cell-permeable analog 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate counteracted the direct activation of phospholipase C by 2,4,6-trimethyl-N43-(trifluoromethyl)phenylbenzenesulfonamide. Hence, by inhibiting production of the protein kinase C activating lipid, diacylglycerol, cAMP/Epac signaling blocks the bottleneck step of the converging pathways of oxidative burst triggering. Manipulation of neutrophil membrane composition by CyaA-produced signaling of cAMP thus enables B. pertussis to evade the key innate host defense mechanism of reactive oxygen species mediated killing of bacteria by neutrophils.
Workplace	Institute of Microbiology
Contact	Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231
Year of Publishing	2018

Number of the records: 1