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Cell Chem Biol. 2018 Jun 21;25(6):691-704.e6. doi: 10.1016/j.chembiol.2018.03.002. Epub 2018 Apr 5.

The Rheumatoid Arthritis-Associated Citrullinome.

Author information

1
Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA.
2
Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
3
Immunology, Janssen Research, Spring House, PA 19477, USA.
4
Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA. Electronic address: paul.thompson@umassmed.edu.

Abstract

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.

KEYWORDS:

ACPA; Serpin; chemoproteomic; citrullination; citrulline; deiminase; enzyme; rheumatoid arthritis

PMID:
29628436
PMCID:
PMC6014894
DOI:
10.1016/j.chembiol.2018.03.002
[Indexed for MEDLINE]
Free PMC Article

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