University of Massachusetts Medical School Faculty Publications

Title

The role of SERPIN citrullination in thrombosis

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2021-12-16

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Cardiovascular Diseases | Enzymes and Coenzymes | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Musculoskeletal Diseases

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

DOI of Published Version

10.1016/j.chembiol.2021.07.009

Source

Tilvawala R, Nemmara VV, Reyes AC, Sorvillo N, Salinger AJ, Cherpokova D, Fukui S, Gutch S, Wagner D, Thompson PR. 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. PMID: 34352225; PMCID: PMC8688209. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Cell chemical biology

PubMed ID

34352225

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