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The role of SERPIN citrullination in thrombosis

Ronak Tilvawala1, Venkatesh V Nemmara2, Archie C Reyes3

  • 1Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.

Cell Chemical Biology
|August 5, 2021
PubMed

Insights

Aberrant protein citrullination, a modification linked to diseases, disrupts serine protease inhibitor (SERPIN) function. This disruption promotes thrombus formation, increasing thrombosis risk in autoimmune conditions.

Area of Science:

  • Biochemistry
  • Pathology
  • Immunology

Background:

  • Aberrant protein citrullination is implicated in various diseases, but its specific functional consequences are not fully understood.
  • Serine protease inhibitors (SERPINs), crucial regulators of coagulation and fibrinolysis, are highly citrullinated in rheumatoid arthritis (RA).
  • Citrullination of SERPINs like antithrombin, antiplasmin, and t-PAI diminishes their inhibitory functions.

Purpose of the Study:

  • To investigate the functional impact of SERPIN citrullination on coagulation and fibrinolysis.
  • To elucidate the role of citrullinated SERPINs in pathological thrombus formation.
  • To establish a link between protein citrullination and thrombosis risk in autoimmune diseases.

Main Methods:

  • In vitro plasma clotting and fibrinolysis assays were employed to assess the functional consequences of SERPIN citrullination.
  • Analysis of citrullinated antithrombin and antiplasmin levels in a deep vein thrombosis (DVT) model.
  • Characterization of the binding interactions between citrullinated SERPINs and their cognate proteases.

Main Results:

  • Citrullination of antithrombin and t-PAI impairs their ability to bind to their target proteases.
  • Citrullination transforms antiplasmin from an inhibitor into a substrate for proteases.
  • In a DVT model, levels of citrullinated antithrombin increased, while citrullinated antiplasmin decreased, shifting the balance towards thrombus formation.

Conclusions:

  • Aberrant citrullination of SERPINs disrupts their regulatory functions in hemostasis.
  • SERPIN citrullination contributes to a pro-thrombotic state, increasing the risk of thrombosis in autoimmune conditions.
  • Targeting protein citrullination may offer a therapeutic strategy for preventing thrombosis in associated pathologies.

Keywords:
citrullinationdeep vein thrombosisrheumatoid arthritisserine protease inhibitors

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