XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta
XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta
XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta
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Lectures<br />
RTX CYTOTOXINS rECOGNIZE β 2<br />
INTEGrIN rECEPTOrs THrOUGH<br />
N-LINKED OLIGOSaCCHarIDES<br />
Jana Morová, Radim Osička, Jiří Mašín and Peter Šebo<br />
Institute of Microbiology of the Academy of Sciences of the Czech Republic,<br />
Czech Republic<br />
Bordetella pertussis Adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) is a bifunctional<br />
protein belonging to the RTX (Repeat in ToXin) family of bacterial cytotoxins.<br />
CyaA delivers into target cells an adenylate cyclase domain, which catalyzes uncontrolled<br />
conversion of ATP to cAMP, a key signaling molecule subverting cell functions. The toxin<br />
utilizes as a specific cellular receptor, the CD11b/CD18 integrin (α M<br />
β 2<br />
, Mac-1, or CR3)<br />
that is heavily Nglycosylated. Here, we demonstrate that deglycosylation of cell surface<br />
proteins by glycosidases completely abolished CyaA binding to CD11b-expressing cells.<br />
Moreover, cAMP intoxication of the deglycosylated cells exposed to the toxin was significantly<br />
reduced, suggesting a requirement of CD11b/CD18 glycosylation. Similar results<br />
were obtained, when N-glycosylation of de novo synthesized cellular proteins was inhibited<br />
by the antibiotic tunicamycin. Moreover, binding of CyaA to CD11b-expressing cells<br />
was significantly inhibited in the presence of excess of free saccharides found in building<br />
units of the oligosaccharide complex of the integrin. On the other hand, saccharides<br />
not occurring in integrin oligosaccharide chains were unable to inhibit CyaA binding to<br />
CD11b/CD18 to any significant extent, showing that CyaA selectively recognizes the sugar<br />
residues of N-linked oligosaccharides of the integrin. Furthermore, the requirement for<br />
integrin glycosylation could be demonstrated also for binding of another RTX protein, the<br />
leukotoxin of Aggregatibacter actinomycetemcomitans (LtxA), which specifically binds<br />
to target cells via another receptor of the β 2<br />
integrin family, CD11a/CD18. These results<br />
demonstrate that glycosylation of β 2<br />
integrin receptors facilitates CyaA and LtxA binding<br />
to and killing of various target cells and set a new paradigm for action of RTX cytotoxins.<br />
82 <strong>XXII</strong>. Biochemistry Congress, Martin
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