Ixonnexin from Tick Saliva Promotes Fibrinolysis by Interacting with Plasminogen and Tissue-Type Plasminogen Activator, and Prevents Arterial Thrombosis

Teresa C. Assumpção, Daniella M. Mizurini, Dongying Ma, Robson Q. Monteiro, Sydney Ahlstedt, Morayma Reyes, Michail Kotsyfakis, Thomas N. Mather, John F. Andersen, Jan Lukszo, José M.C. Ribeiro, Ivo M.B. Francischetti

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6 Scopus citations

Abstract

Tick saliva is a rich source of modulators of vascular biology. We have characterized Ixonnexin, a member of the "Basic-tail" family of salivary proteins from the tick Ixodes scapularis. Ixonnexin is a 104 residues (11.8 KDa), non-enzymatic basic protein which contains 3 disulfide bonds and a C-terminal rich in lysine. It is homologous to SALP14, a tick salivary FXa anticoagulant. Ixonnexin was produced by ligation of synthesized fragments (51-104) and (1-50) followed by folding. Ixonnexin, like SALP14, interacts with FXa. Notably, Ixonnexin also modulates fibrinolysis in vitro by a unique salivary mechanism. Accordingly, it accelerates plasminogen activation by tissue-type plasminogen activator (t-PA) with Km 100 nM; however, it does not affect urokinase-mediated fibrinolysis. Additionally, lysine analogue ϵ-aminocaproic acid inhibits Ixonnexin-mediated plasmin generation implying that lysine-binding sites of Kringle domain(s) of plasminogen or t-PA are involved in this process. Moreover, surface plasmon resonance experiments shows that Ixonnexin binds t-PA, and plasminogen (KD 10 nM), but not urokinase. These results imply that Ixonnexin promotes fibrinolysis by supporting the interaction of plasminogen with t-PA through formation of an enzymatically productive ternary complex. Finally, in vivo experiments demonstrates that Ixonnexin inhibits FeCl3-induced thrombosis in mice. Ixonnexin emerges as novel modulator of fibrinolysis which may also affect parasite-vector-host interactions.

Original languageEnglish (US)
Article number4806
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

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    Assumpção, T. C., Mizurini, D. M., Ma, D., Monteiro, R. Q., Ahlstedt, S., Reyes, M., Kotsyfakis, M., Mather, T. N., Andersen, J. F., Lukszo, J., Ribeiro, J. M. C., & Francischetti, I. M. B. (2018). Ixonnexin from Tick Saliva Promotes Fibrinolysis by Interacting with Plasminogen and Tissue-Type Plasminogen Activator, and Prevents Arterial Thrombosis. Scientific reports, 8(1), [4806]. https://doi.org/10.1038/s41598-018-22780-1