Adenylate cyclase toxin in virulence of the pertussis agent

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F25%3A00643268" target="_blank" >RIV/61388971:_____/25:00643268 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Adenylate cyclase toxin in virulence of the pertussis agent

Popis výsledku v původním jazyce

The capacity of classical Bordetella species to cause respiratory infections in mammals involves the production of an RTX family adenylate cyclase toxin-cytolysin (ACT, AC-Hly, or CyaA). This bifunctional fatty-acylated and T1SS-excreted toxin is a 1706 residue-long fusion of a cytotoxic N-terminal adenylyl cyclase (AC) enzyme (~400 residues) with a prototypic C-terminal Repeat-in-ToXin (RTX) cytolysin (Hly) moiety (~1306 residues). Hly binds the CD11b subunit of the αMβb2 (CD11b/CD18) integrin serving as the complement receptor 3 (CR3) of sentinel myeloid phagocytic cells. Following CD11b binding, CyaA penetrates the plasma membrane of phagocytes, forms small cation-selective pores and delivers the AC enzyme into the cytosol of phagocytes. There, the AC is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cAMP. This hijacks cellular signaling pathways and near-instantly ablates the bactericidal functions of host sentinel phagocytes. I will summarize our studies on the structure-function relationships that underlie CyaA toxin action, such as (i) toxin activation attachment of by fatty-acyl chains, (ii) calcium binding-driven vectorial folding of the RTX domain and (iii) the role of acylated β-hairpins in membrane insertion of CyaA. I will conclude by discussing how the epigenetic reprogramming elicited by CyaA/cAMP signaling in monocytes, suppresses the transcriptional pro-differentiation program of monocytes, to block their transition into bactericidal macrophage cells.

Název v anglickém jazyce

Adenylate cyclase toxin in virulence of the pertussis agent

Popis výsledku anglicky

The capacity of classical Bordetella species to cause respiratory infections in mammals involves the production of an RTX family adenylate cyclase toxin-cytolysin (ACT, AC-Hly, or CyaA). This bifunctional fatty-acylated and T1SS-excreted toxin is a 1706 residue-long fusion of a cytotoxic N-terminal adenylyl cyclase (AC) enzyme (~400 residues) with a prototypic C-terminal Repeat-in-ToXin (RTX) cytolysin (Hly) moiety (~1306 residues). Hly binds the CD11b subunit of the αMβb2 (CD11b/CD18) integrin serving as the complement receptor 3 (CR3) of sentinel myeloid phagocytic cells. Following CD11b binding, CyaA penetrates the plasma membrane of phagocytes, forms small cation-selective pores and delivers the AC enzyme into the cytosol of phagocytes. There, the AC is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cAMP. This hijacks cellular signaling pathways and near-instantly ablates the bactericidal functions of host sentinel phagocytes. I will summarize our studies on the structure-function relationships that underlie CyaA toxin action, such as (i) toxin activation attachment of by fatty-acyl chains, (ii) calcium binding-driven vectorial folding of the RTX domain and (iii) the role of acylated β-hairpins in membrane insertion of CyaA. I will conclude by discussing how the epigenetic reprogramming elicited by CyaA/cAMP signaling in monocytes, suppresses the transcriptional pro-differentiation program of monocytes, to block their transition into bactericidal macrophage cells.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10606 - Microbiology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů