The Rheumatoid Arthritis-Associated Citrullinome
| Autor: | Mitesh Nagar, Aaron J. Maurais, Venkatesh V. Nemmara, Sunil Nagpal, Ari J. Salinger, Paul R. Thompson, Ronak Tilvawala, Eranthie Weerapana, Son Hong Nguyen |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Proteomics
0301 basic medicine Proteases medicine.medical_treatment Clinical Biochemistry Filaggrin Proteins Serpin Biology Biochemistry Protein citrullination Article Arthritis Rheumatoid 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Citrulline medicine Humans Molecular Biology Pharmacology Protease Citrullination Protein-arginine deiminase 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer research Molecular Medicine Filaggrin |
| Zdroj: | Cell Chemical Biology. 25:691-704.e6 |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2018.03.002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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