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Authors
Tilvawala, RonakNguyen, Son Hong
Maurais, Aaron J
Nemmara, Venkatesh V.
Nagar, Mitesh
Salinger, Ari J.
Nagpal, Sunil
Weerapana, Eranthie
Thompson, Paul R
Document Type
Journal ArticlePublication Date
2018-06-21Keywords
citrullineACPA
deiminase
rheumatoid arthritis
chemoproteomic
enzyme
citrullination
Serpin
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Musculoskeletal Diseases
Rheumatology
Metadata
Show full item recordAbstract
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.Source
Cell Chem Biol. 2018 Jun 21;25(6):691-704.e6. doi: 10.1016/j.chembiol.2018.03.002. Epub 2018 Apr 5.
DOI
10.1016/j.chembiol.2018.03.002Permanent Link to this Item
http://hdl.handle.net/20.500.14038/46452PubMed ID
29628436Related Resources
ae974a485f413a2113503eed53cd6c53
10.1016/j.chembiol.2018.03.002