Loos Tamara, Mortier Anneleen, Gouwy Mieke, Ronsse Isabelle, Put Willy, Lenaerts Jean-Pierre, Van Damme Jo, Proost Paul
Laboratory of Molecular Immunology, Rega Institute, KU (Katholieke Universiteit) Leuven, Leuven, Belgium.
Blood. 2008 Oct 1;112(7):2648-56. doi: 10.1182/blood-2008-04-149039. Epub 2008 Jul 21.
Interactions between chemokines and enzymes are vital in immunoregulation. Structural protein citrullination by peptidylarginine deiminase (PAD) has been associated with autoimmunity. In this report, we identified a novel naturally occurring posttranslational modification of chemokines, that is, the deimination of arginine at position 5 into citrulline of CXC chemokine ligand 10 (CXCL10) by rabbit PAD and human PAD2. Citrullination reduced (>/= 10-fold) the chemoattracting and signaling capacity of CXCL10 for CXC chemokine receptor 3 (CXCR3) transfectants; however, it did not affect CXCR3 binding. On T lymphocytes, though, citrullinated CXCL10 remained active but was again weaker than authentic CXCL10. PAD was also able to convert CXCL11, causing an impairment of CXCR3 signaling and T-cell activation, though less pronounced than for CXCL10. Similarly, receptor binding properties of CXCL11 were not altered by citrullination. However, deimination decreased heparin binding properties of both CXCL10 and CXCL11. Overall, chemokines are the first immune modulators reported of being functionally modified by citrullination. These data provide new structure-function dimensions for chemokines in leukocyte mobilization, disclosing an anti-inflammatory role for PAD. Additionally because citrullination has severe consequences for chemokine biology, this invites to reassess the involvement and impact of PAD and citrullinated peptides in inflammation, autoimmunity, and hematologic disorders.
趋化因子与酶之间的相互作用在免疫调节中至关重要。肽基精氨酸脱亚氨酶（PAD）介导的结构蛋白瓜氨酸化与自身免疫有关。在本报告中，我们鉴定出一种新型的趋化因子天然存在的翻译后修饰，即兔PAD和人PAD2将CXC趋化因子配体10（CXCL10）第5位的精氨酸脱亚氨生成瓜氨酸。瓜氨酸化降低（≥10倍）了CXCL10对CXC趋化因子受体3（CXCR3）转染细胞的趋化和信号传导能力；然而，它并不影响CXCR3的结合。不过，在T淋巴细胞上，瓜氨酸化的CXCL10仍保持活性，但再次弱于天然CXCL10。PAD也能够使CXCL11发生转化，导致CXCR3信号传导和T细胞活化受损，尽管不如对CXCL10那么明显。同样，瓜氨酸化并未改变CXCL11的受体结合特性。然而，脱亚氨作用降低了CXCL10和CXCL11两者的肝素结合特性。总体而言，趋化因子是首个被报道可通过瓜氨酸化进行功能修饰的免疫调节剂。这些数据为趋化因子在白细胞动员中的作用提供了新的结构 - 功能维度，揭示了PAD的抗炎作用。此外，由于瓜氨酸化对趋化因子生物学有严重影响，这促使人们重新评估PAD和瓜氨酸化肽在炎症、自身免疫和血液系统疾病中的参与情况及影响。
