The Rheumatoid Arthritis-Associated Citrullinome.
Thompson Lab; Department of Biochemistry and Molecular Pharmacology
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Musculoskeletal Diseases | Rheumatology
Increased protein citrullination is linked to various diseases including rheumatoid arthritis (RA), lupus, and cancer. Citrullinated autoantigens, a hallmark of RA, are recognized by anti-citrullinated protein antibodies (ACPAs) which are used to diagnose RA. ACPA-recognizing citrullinated enolase, vimentin, keratin, and filaggrin are also pathogenic. Here, we used a chemoproteomic approach to define the RA-associated citrullinome. The identified proteins include numerous serine protease inhibitors (Serpins), proteases and metabolic enzymes. We demonstrate that citrullination of antiplasmin, antithrombin, t-PAI, and C1 inhibitor (P1-Arg-containing Serpins) abolishes their ability to inhibit their cognate proteases. Citrullination of nicotinamide N-methyl transferase (NNMT) also abolished its methyltransferase activity. Overall, these data advance our understanding of the roles of citrullination in RA and suggest that extracellular protein arginine deiminase (PAD) activity can modulate protease activity with consequent effects on Serpin-regulated pathways. Moreover, our data suggest that inhibition of extracellular PAD activity will be therapeutically relevant.
citrulline, ACPA, deiminase, rheumatoid arthritis, chemoproteomic, enzyme, citrullination, Serpin
DOI of Published Version
Cell Chem Biol. 2018 Jun 21;25(6):691-704.e6. doi: 10.1016/j.chembiol.2018.03.002. Epub 2018 Apr 5.
Cell Chemical Biology
Tilvawala, Ronak; Nguyen, Son Hong; Maurais, Aaron J; Nemmara, Venkatesh V.; Nagar, Mitesh; Salinger, Ari J.; Nagpal, Sunil; Weerapana, Eranthie; and Thompson, Paul R., "The Rheumatoid Arthritis-Associated Citrullinome." (2018). University of Massachusetts Medical School Publications. 9.