The role of SERPIN citrullination in thrombosis

Ronak Tilvawala; Venkatesh V Nemmara; Archie C Reyes; Nicoletta Sorvillo; Ari J Salinger; Deya Cherpokova; Saeko Fukui; Sarah Gutch; Denisa Wagner; Paul R Thompson

doi:10.1016/j.chembiol.2021.07.009

The role of SERPIN citrullination in thrombosis

Cell Chem Biol. 2021 Dec 16;28(12):1728-1739.e5. doi: 10.1016/j.chembiol.2021.07.009. Epub 2021 Aug 4.

Authors

Affiliations

¹ Department 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.
² Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA; Department of Chemistry, Rowan University, Glassboro, NJ 08028, USA.
³ Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA.
⁴ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁵ Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA; Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
⁶ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Whitman Center, Marine Biological Laboratory, Woods Hole, MA 02543, USA.
⁷ Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA. Electronic address: paul.thompson@umassmed.edu.

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.

Keywords: citrullination; deep vein thrombosis; rheumatoid arthritis; serine protease inhibitors.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antifibrinolytic Agents / chemistry
Antifibrinolytic Agents / pharmacology*
Antithrombins / chemistry
Antithrombins / pharmacology*
Disease Models, Animal
Female
Male
Mice
Mice, Inbred C57BL
Peptide Hydrolases / metabolism
Plasminogen Inactivators / chemistry
Plasminogen Inactivators / pharmacology*
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology*
Venous Thrombosis / drug therapy*
Venous Thrombosis / metabolism

Substances

Antifibrinolytic Agents
Antithrombins
Plasminogen Inactivators
Serine Proteinase Inhibitors
Peptide Hydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding