Citrullinated Fibrinogen Inhibits Thrombin-catalysed Fibrin Polymerization

Abstract

Citrullination is the post-translational modification of arginine residues by peptidylarginine deiminases (PADIs). Fibrinogen is one substrate of PADIs under physiological conditions. Fibrinogen is an important factor for blood coagulation and inducing inflammation. The citrullinated form of fibrinogen appears in rheumatoid arthritis synovial tissue together with the production of autoantibodies that target self-peptides containing citrulline. However, whether the function of fibrinogen changes after citrullination remains unclear. We found that citrullinated fibrinogen markedly impairs the function of thrombin-catalysed fibrin polymerization and also inhibits fibrin formation. Increased citrullinated fibrinogen might thus affect the balance between coagulation and fibrinolysis and alter antigenicity under physiological conditions. These data suggest that citrullination of proteins could physiologically change functions and subsequently generate pro-inflammatory conditions and autoimmune reactions.

Neuronal PAD4 expression and protein citrullination: Possible role in production of autoantibodies associated with neurodegenerative disease

“…Given this seemingly global expression of PADs, some of which is apparently independent of disease states, it is likely that citrullinated proteins have many hitherto unknown non-pathological roles [2,5,36]. For example, citrullinated chemoattractants have been shown to reduce the extravasation of leukocytes as the citrullinated form of chemoattractants is unable to attract neutrophils [5,40e42] and citrullinated fibrinogen influences coagulation [43,44]. However, there are also many known pathological implications of citrullinated proteins other than RA.…”

Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization catalyzed by thrombin

“…Most recently, Nakayama-Hamada et al [16] reported that no FPA or FPB release and no polymerization of citrullinated fibrinogen were observed after thrombin stimulation. Moreover, they also demonstrated that citrullinated fibrinogen 8 and a synthetic peptide that mimics citrullinated FPA inhibit thrombin-catalyzed fibrin polymerization.…”

Citrullination – small change with a great consequence

“…Damaged cell products stimulate the retraction of endothelial cells, which facilitates the extravasation of fibrinogen and other plasma components (Méchin et al 2007). Citrullination can indeed occur within the rheumatoid synovial tissue with many different L-Arg residues citrullinated in different proteins including fibrinogen (Okumura et al 2009;Vossenaar 2004 (Nakayama-Hamada et al 2008). In addition, certain fibrinogen molecules can be converted to fibrin before deimination.…”

“…The advanced degree of citrullination leads to denaturation of the protein (Tarcsa et al 1996a;Vossenaar et al 2003;Chang et al 2005;Nakayama-Hamada et al 2008). …”