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.

中文翻译：

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类风湿关节炎相关瓜氨酸

蛋白质瓜氨酸化程度增加与各种疾病有关，包括类风湿性关节炎（RA），狼疮和癌症。瓜氨酸化自身抗原是RA的标志，可被用于诊断RA的抗瓜氨酸化蛋白抗体（ACPA）识别。可以识别ACPA的瓜氨酸化烯醇化酶，波形蛋白，角蛋白和丝聚蛋白也具有致病性。在这里，我们使用一种化学旋转方法来定义RA相关的瓜氨酸组。鉴定出的蛋白质包括许多丝氨酸蛋白酶抑制剂（Serpins），蛋白酶和代谢酶。我们证明抗纤溶酶，抗凝血酶，t-PAI和C1抑制剂（含P1-Arg的丝氨酸蛋白酶抑制剂）的瓜氨酸化消除了它们抑制其同源蛋白酶的能力。烟酰胺N-甲基转移酶（NNMT）的瓜氨酸化也取消了其甲基转移酶活性。全面的，这些数据提高了我们对瓜氨酸在RA中的作用的理解，并表明细胞外蛋白精氨酸脱亚氨酶（PAD）活性可以调节蛋白酶活性，从而对Serpin调节的途径产生影响。此外，我们的数据表明抑制细胞外PAD活性与治疗有关。