The role of SERPIN citrullination in thrombosis.
Cell Chem Biol
; 28(12): 1728-1739.e5, 2021 12 16.
Article
en En
| MEDLINE
| ID: mdl-34352225
ABSTRACT
Aberrant protein citrullination is associated with many pathologies; however, the specific effects of this modification remain unknown. We have previously demonstrated that serine protease inhibitors (SERPINs) are highly citrullinated in rheumatoid arthritis (RA) patients. These citrullinated SERPINs include antithrombin, antiplasmin, and t-PAI, which regulate the coagulation and fibrinolysis cascades. Notably, citrullination eliminates their inhibitory activity. Here, we demonstrate that citrullination of antithrombin and t-PAI impairs their binding to their cognate proteases. By contrast, citrullination converts antiplasmin into a substrate. We recapitulate the effects of SERPIN citrullination using in vitro plasma clotting and fibrinolysis assays. Moreover, we show that citrullinated antithrombin and antiplasmin are increased and decreased in a deep vein thrombosis (DVT) model, accounting for how SERPIN citrullination shifts the equilibrium toward thrombus formation. These data provide a direct link between increased citrullination and the risk of thrombosis in autoimmunity and indicate that aberrant SERPIN citrullination promotes pathological thrombus formation.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Inactivadores Plasminogénicos
/
Inhibidores de Serina Proteinasa
/
Antitrombinas
/
Trombosis de la Vena
/
Antifibrinolíticos
Límite:
Animals
Idioma:
En
Revista:
Cell Chem Biol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos