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
Journal/Book/Conference Title
Cell chemical biology
PubMed ID
34352225
Repository Citation
Tilvawala R, Nemmara VV, Reyes AC, Sorvillo N, Salinger AJ, Cherpokova D, Fukui S, Gutch S, Wagner D, Thompson PR. (2021). The role of SERPIN citrullination in thrombosis. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1016/j.chembiol.2021.07.009. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/2131