Metzemaekers Mieke, Van Damme Jo, Mortier Anneleen, Proost Paul
Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven , Leuven , Belgium.
Front Immunol. 2016 Nov 11;7:483. doi: 10.3389/fimmu.2016.00483. eCollection 2016.
Chemokines are small, chemotactic proteins that play a crucial role in leukocyte migration and are, therefore, essential for proper functioning of the immune system. Chemokines exert their chemotactic effect by activation of chemokine receptors, which are G protein-coupled receptors (GPCRs), and interaction with glycosaminoglycans (GAGs). Furthermore, the exact chemokine function is modulated at the level of posttranslational modifications. Among the different types of posttranslational modifications that were found to occur and , i.e., proteolysis, citrullination, glycosylation, and nitration, NH-terminal proteolysis of chemokines has been described most intensively. Since the NH-terminal chemokine domain mediates receptor interaction, NH-terminal modification by limited proteolysis or amino acid side chain modification can drastically affect their biological activity. An enzyme that has been shown to provoke NH-terminal proteolysis of various chemokines is dipeptidyl peptidase IV or CD26. This multifunctional protein is a serine protease that preferably cleaves dipeptides from the NH-terminal region of peptides and proteins with a proline or alanine residue in the penultimate position. Various chemokines possess such a proline or alanine residue, and CD26-truncated forms of these chemokines have been identified in cell culture supernatant as well as in body fluids. The effects of CD26-mediated proteolysis in the context of chemokines turned out to be highly complex. Depending on the chemokine ligand, loss of these two NH-terminal amino acids can result in either an increased or a decreased biological activity, enhanced receptor specificity, inactivation of the chemokine ligand, or generation of receptor antagonists. Since chemokines direct leukocyte migration in homeostatic as well as pathophysiologic conditions, CD26-mediated proteolytic processing of these chemotactic proteins may have significant consequences for appropriate functioning of the immune system. After introducing the chemokine family together with the GPCRs and GAGs, as main interaction partners of chemokines, and discussing the different forms of posttranslational modifications, this review will focus on the intriguing relationship of chemokines with the serine protease CD26.
趋化因子是一类小分子趋化蛋白，在白细胞迁移中起关键作用，因此对免疫系统的正常运作至关重要。趋化因子通过激活趋化因子受体发挥其趋化作用，趋化因子受体是G蛋白偶联受体（GPCRs），并与糖胺聚糖（GAGs）相互作用。此外，趋化因子的确切功能在翻译后修饰水平上受到调节。在已发现的不同类型的翻译后修饰中，即蛋白水解、瓜氨酸化、糖基化和硝化，趋化因子的N端蛋白水解得到了最深入的描述。由于趋化因子的N端结构域介导受体相互作用，有限的蛋白水解或氨基酸侧链修饰引起的N端修饰可极大地影响其生物学活性。已证明能引发多种趋化因子N端蛋白水解的一种酶是二肽基肽酶IV或CD26。这种多功能蛋白是一种丝氨酸蛋白酶，它优先从倒数第二位含有脯氨酸或丙氨酸残基的肽和蛋白质的N端区域切割二肽。多种趋化因子具有这样的脯氨酸或丙氨酸残基，并且在细胞培养上清液以及体液中已鉴定出这些趋化因子的CD26截短形式。事实证明，CD26介导的趋化因子蛋白水解作用非常复杂。取决于趋化因子配体，这两个N端氨基酸的缺失可能导致生物学活性增加或降低、受体特异性增强、趋化因子配体失活或受体拮抗剂的产生。由于趋化因子在稳态以及病理生理条件下指导白细胞迁移，CD26介导的这些趋化蛋白的蛋白水解加工可能对免疫系统的正常运作产生重大影响。在介绍了趋化因子家族以及作为趋化因子主要相互作用伙伴的GPCRs和GAGs，并讨论了不同形式的翻译后修饰之后，本综述将重点关注趋化因子与丝氨酸蛋白酶CD26之间的有趣关系。
