CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders Chenyang Lu,*,† Mohammad A
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CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders Chenyang Lu,*,† Mohammad A. Amin,* and David A. Fox* CD13/aminopeptidase N is a widely expressed ectoen- and processing of inflammatory mediators, which are im- zyme with multiple functions. As an enzyme, CD13 portant features of immune responses. In this study, we regulates activities of numerous cytokines by cleaving review evidence concerning the involvement of CD13, includ- their N-terminals and is involved in Ag processing by ing a soluble form of the molecule in inflammation and its trimming the peptides bound to MHC class II. Inde- potential as a therapeutic target in inflammatory disorders. pendent of its enzymatic activity, cell membrane CD13 functions by cross-linking–induced signal transduc- Mechanisms of CD13 functions tion, regulation of receptor recycling, enhancement of CD13 was named aminopeptidase N because of its prefer- FcgR-mediated phagocytosis, and acting as a receptor ence for binding neutral amino acids and because it removes for cytokines. Moreover, soluble CD13 has multiple N-terminal amino acids from unsubstituted oligopeptides, proinflammatory roles mediated by binding to G-pro- with the exception of peptides with proline in the penulti- tein–coupled receptors. CD13 not only modulates de- mate position (11). By cleaving N termini, CD13 regulates velopment and activities of immune-related cells, but activity of numerous hormones,cytokines,andchemokines also regulates functions of inflammatory mediators. that participate in inflammation. Moreover, CD13 is coex- Therefore, CD13 is important in the pathogenesis of pressed by MHC class II (MHC II)–bearing APCs (12), and is various inflammatory disorders. Inhibitors of CD13 involved in the trimming of MHC II–associated peptides on the have shown impressive anti-inflammatory effects, but surface of APCs (5, 13, 14) (Fig. 1). none of them has yet been used for clinical therapy of SomeCD13functionsintheimmunesystemareinde- human inflammatory diseases. We reevaluate CD13’s pendent of its enzymatic activity. These mechanisms include regulatory role in inflammation and suggest that CD13 cross-linking–induced signal transduction (15), enhancement of FcgR-mediated phagocytosis (16), acting as a receptor could be a potential therapeutic target for inflamma- (17, 18), and binding of soluble CD13 (sCD13) to G-protein– tory disorders. The Journal of Immunology, 2020, by guest on October 1, 2021. Copyright 2019 Pageant Media Ltd. coupled receptors (GPCRs) (19) (Fig. 1). 204: 3–11. Various cellular responses, including homotypic aggrega- tion, cell–cell adhesion, and migration, have been observed D13, also known as aminopeptidase N or membrane after cross-linking CD13 with mAbs. Interestingly, CD13, alanyl aminopeptidase, is a type II membrane, 150- which includes a 7-aa cytoplasmic tail that was previously as- C kDa metalloprotease with an extracellular-oriented sumed to be inert, is itself phosphorylated in a Src-dependent catalytic domain. It is a seahorse-shaped molecule and manner (20). mAb cross-linking of CD13 induces clustering usually forms a head-to-head homodimer by means of and phosphorylation of tyrosine 6 in the cytoplasmic domain hydrophobic interactions (1, 2). Each monomeric molecule of CD13, activation of Src, FAK, ERK, and potentially other http://classic.jimmunol.org of CD13 possesses a seven-domain organization, which is components of the Ras/MAPK (JNK and p38) and PI3K characteristic of M1 metallopeptidases (1, 3). CD13 has pathways. Initiation of a Ca2+ flux by mAb against CD13 results been termed a “moonlighting enzyme” because of its in increased adhesion of monocytes (MNs) to endothelial cells multiple functions (4). Increasing evidence points to cru- (ECs) or to a monolayer of CD13 and upregulation of cyto- cial regulatory functions for CD13 during normal and kines including IL-8 (15, 20). Anti-CD13 mAbs also induce pathologic immune responses. CD13 has been suggested to integrin-independent homotypic aggregation of monocytic Downloaded from play a role in Ag processing (5, 6), cell trafficking (7–10) U937 cells independent of their effects on CD13’s enzymatic *Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Abbreviations used in this article: a.k.a, also known as; ARF6, adenosine diphosphate Michigan Medical School, Ann Arbor, MI 48109; and †Department of Rheumatology ribosylation factor 6; BK, bradykinin; DP IV, dipeptidyl peptidase IV; EAE, experimen- and Immunology, West China Hospital, Sichuan University, Chengdu 610041, tal autoimmune encephalomyelitis; EC, endothelial cell; FLS, fibroblast-like synoviocyte; Sichuan, China GPCR, G-protein–coupled receptor; HCMV, human CMV; IBD, inflammatory bowel disease; ILD, interstitial lung disease; IL-1RA, IL-1R antagonist; IQGAP1, IQ motif Received for publication July 23, 2019. Accepted for publication October 1, 2019. containing GTPase activating protein 1; MHC II, MHC class II; MMP, matrix metal- This work was supported by a National Institute of Allergy and Infectious Diseases loproteinase; MN, monocyte; MS, multiple sclerosis; OA, osteoarthritis; RA, rheuma- Clinical Autoimmunity Center of Excellence Award. toid arthritis; sCD13, soluble CD13; Treg, regulatory T. Address correspondence and reprint requests to Dr. David A. Fox, Department of Ó Internal Medicine/Division of Rheumatology, University of Michigan Medical School, Copyright 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 3918 Taubman Center, 1500 E. Medical Center Drive, SPC 5358, 7C27 North Ingalls Building, Ann Arbor, MI 48109-5422. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900868 4 BRIEF REVIEWS: CD13 IS A THERAPEUTIC TARGET FOR INFLAMMATORY DISORDERS FIGURE 1. Mechanisms of CD13 functions. CD13 acts by enzyme-dependent mechanisms and enzyme-independent mechanisms. CD13 can cleave the N terminus of numerous cytokines, hormones, and chemokines and trim peptides that bind to MHC II. Ab cross-linking of CD13 induces clustering of CD13, tyrosine phosphorylation of CD13, and activation of Src kinase, FAK and ERK kinases, a calcium flux, and potentially other components of the Ras/MAPK and PI3K pathways, resulting in increased adhesion of MNs to endothelial or monolayer CD13. CD13 also tethers the IQGAP1–ARF6–EFA6 complex on the plasma membrane to promote ARF6 activation, b1 integrin recycling, and cell migration. CD13 functionally interacts with FcgRs and enhances phagocytosis by in- creasing the level and duration of Syk phosphorylation. CD13 is a cell surface receptor for some cytokines, such as 14-3-3 proteins, signaling via p38 MAPK and JNK. CD13 can be shed from the cell membrane and sCD13 functions through engagement of GPCRs. ECM, extracellular matrix; ER, endoplasmic reticulum. by guest on October 1, 2021. Copyright 2019 Pageant Media Ltd. activity (7). Such CD13-induced cell–cell adhesion is also by increasing the level and duration of Syk phosphorylation dependent on the carbohydrate-binding protein galectin-3. A induced by FcgRs themselves (16). There is a possibility that possible mechanism could be that Ab cross-linking of CD13 CD13 positively modulates FcgR-mediated signals and triggers a signaling cascade leading to release of galectin-3, functions when CD13 and FcgR bind to their ligands, as which then binds to another receptor and triggers adhesion CD13 is a well-known receptor for viral proteins and other or, in oligomeric form, binds to glycoconjugates on neigh- pathogen-derived molecules. Moreover, CD13 was reported boring cells (21). CD13 can be constitutively phosphorylated to be a cell-surface receptor for some cytokines, including 14- http://classic.jimmunol.org at Tyr6 (10, 20) to interact with IQ motif containing GTPase 3-3e and 14-3-3s (also known as [a.k.a] stratifin) (17, 18). By activating protein 1 (IQGAP1), a scaffold protein that interacts binding to CD13 on cells such as fibroblasts and chon- with over 90 other proteins to mediate biological functions drocytes, 14-3-3e regulates production of matrix-degrading (22). CD13 serves to properly position IQGAP1 to perform enzymes such as matrix metalloproteinases (MMP)–3 and its functions; thus, it was expected that CD13 participates –13 through p38 MAPKs and JNK-signaling cascades, whereas in numerous functions mediated by IQGAP1, including cell 14-3-3s induces expression of MMP-1 through p38 MAPK Downloaded from motility, endocytosis, filopodia formation, angiogenesis, and activation (17, 18). Phosphorylation of the ectodomains of phagocytosis (10). A recent study demonstrated that CD13 can CD13 augments the binding affinity of 14-3-3 proteins to tether IQGAP1 with active adenosine diphosphate ribosylation CD13, regulating the downstream signaling cascade. It has factor 6 (ARF6) and b1 integrin at the plasma membrane to been proposed that enzymatic activity and binding to extra- allow b1 integrin recycling and cell migration (10). However, cellular matrix proteins through Asn–Gly–Arg motifs is me- mAbs binding to distinct epitopes of CD13 mediate dif- diated through the catalytic site involving domains IV–VII; ferent consequences for cell adhesion. For example, cross- cell–cell adhesion is mediated by the C-terminal part, in- linking CD13 by some mAbs inhibits cell adhesion, whereas volving half of domain VI and VII, whereas signal transduc- mAb 452 induces it (23). tion depends on the transmembrane and cytoplasmic domains CD13 colocalizes with FcgRs, including FcgRII/CD32 and (I and II)