Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells

0483846 - MBÚ 2018 RIV GB eng J - Journal Article
Novák, Jakub - Fabrik, I. - Linhartová, Irena - Link, M. - Černý, Ondřej - Stulík, J. - Šebo, Peter
Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells.
Scientific Reports. Roč. 7, NOV 24 (2017), č. článku 16298. ISSN 2045-2322. E-ISSN 2045-2322
R&D Projects: GA MZd(CZ) NV16-28126A; GA ČR(CZ) GA13-14547S
Institutional support: RVO:61388971
Keywords : GTPASE-ACTIVATING-PROTEIN * SALT-INDUCIBLE KINASES * GENE ONTOLOGY
OECD category: Microbiology
Impact factor: 4.122, year: 2017

The adenylate cyclase toxin (CyaA) of the whooping cough agent Bordetella pertussis subverts immune functions of host myeloid cells expressing the alpha(M)beta(2) integrin (CD11b/CD18, CR3 or Mac-1). CyaA delivers into cytosol of cells an extremely catalytically active adenylyl cyclase enzyme, which disrupts the innate and adaptive immune functions of phagocytes through unregulated production of the key signaling molecule cAMP. We have used phosphoproteomics to analyze cAMP signaling of CyaA in murine bone marrow-derived dendritic cells. CyaA action resulted in alterations of phosphorylation state of a number of proteins that regulate actin cytoskeleton homeostasis, including Mena, Talin-1 and VASP. CyaA action repressed mTOR signaling through activation of mTORC1 inhibitors TSC2 and PRAS40 and altered phosphorylation of multiple chromatin remodelers, including the class II histone deacetylase HDAC5. CyaA toxin action further elicited inhibitory phosphorylation of SIK family kinases involved in modulation of immune response and provoked dephosphorylation of the transcriptional coactivator CRTC3, indicating that CyaA-promoted nuclear translocation of CRTC3 may account for CyaA-induced IL-10 production. These findings document the complexity of subversive physiological manipulation of myeloid phagocytes by the CyaA toxin, serving in immune evasion of the pertussis agent.
Permanent Link: http://hdl.handle.net/11104/0279008