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• W3189100137 abstract "Multifunctionality of tissue inhibitor of metalloproteinases-1 (TIMP-1) comprising antiproteolytic as well as cytokinic activity has been attributed to its N-terminal and C-terminal domains, respectively. The molecular basis of the emerging proinflammatory cytokinic activity of TIMP-1 is still not completely understood. The cytokine receptor invariant chain (CD74) is involved in many inflammation-associated diseases and is highly expressed by immune cells. CD74 triggers zeta chain–associated protein kinase-70 (ZAP-70) signaling–associated activation upon interaction with its only known ligand, the macrophage migration inhibitory factor. Here, we demonstrate TIMP-1–CD74 interaction by coimmunoprecipitation and confocal microscopy in cells engineered to overexpress CD74. In silico docking in HADDOCK predicted regions of the N-terminal domain of TIMP-1 (N-TIMP-1) to interact with CD74. This was experimentally confirmed by confocal microscopy demonstrating that recombinant N-TIMP-1 lacking the entire C-terminal domain was sufficient to bind CD74. Interaction of TIMP-1 with endogenously expressed CD74 was demonstrated in the Namalwa B lymphoma cell line by dot blot binding assays as well as confocal microscopy. Functionally, we demonstrated that TIMP-1–CD74 interaction triggered intracellular ZAP-70 activation. N-TIMP-1 was sufficient to induce ZAP-70 activation and interference with the cytokine-binding site of CD74 using a synthetic peptide–abrogated TIMP-1-mediated ZAP-70 activation. Altogether, we here identified CD74 as a receptor and mediator of cytokinic TIMP-1 activity and revealed TIMP-1 as moonlighting protein harboring both cytokinic and antiproteolytic activity within its N-terminal domain. Recognition of this functional TIMP-1–CD74 interaction may shed new light on clinical attempts to therapeutically target ligand-induced CD74 activity in cancer and other inflammatory diseases. Multifunctionality of tissue inhibitor of metalloproteinases-1 (TIMP-1) comprising antiproteolytic as well as cytokinic activity has been attributed to its N-terminal and C-terminal domains, respectively. The molecular basis of the emerging proinflammatory cytokinic activity of TIMP-1 is still not completely understood. The cytokine receptor invariant chain (CD74) is involved in many inflammation-associated diseases and is highly expressed by immune cells. CD74 triggers zeta chain–associated protein kinase-70 (ZAP-70) signaling–associated activation upon interaction with its only known ligand, the macrophage migration inhibitory factor. Here, we demonstrate TIMP-1–CD74 interaction by coimmunoprecipitation and confocal microscopy in cells engineered to overexpress CD74. In silico docking in HADDOCK predicted regions of the N-terminal domain of TIMP-1 (N-TIMP-1) to interact with CD74. This was experimentally confirmed by confocal microscopy demonstrating that recombinant N-TIMP-1 lacking the entire C-terminal domain was sufficient to bind CD74. Interaction of TIMP-1 with endogenously expressed CD74 was demonstrated in the Namalwa B lymphoma cell line by dot blot binding assays as well as confocal microscopy. Functionally, we demonstrated that TIMP-1–CD74 interaction triggered intracellular ZAP-70 activation. N-TIMP-1 was sufficient to induce ZAP-70 activation and interference with the cytokine-binding site of CD74 using a synthetic peptide–abrogated TIMP-1-mediated ZAP-70 activation. Altogether, we here identified CD74 as a receptor and mediator of cytokinic TIMP-1 activity and revealed TIMP-1 as moonlighting protein harboring both cytokinic and antiproteolytic activity within its N-terminal domain. Recognition of this functional TIMP-1–CD74 interaction may shed new light on clinical attempts to therapeutically target ligand-induced CD74 activity in cancer and other inflammatory diseases. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a soluble metalloproteinase inhibitor, which is found at high concentrations in the circulation of patients suffering from inflammation-associated diseases (1Lorente L. Martín M.M. Solé-Violán J. Blanquer J. Labarta L. Díaz C. Borreguero-León J.M. Orbe J. Rodríguez J.A. Jiménez A. Páramo J.A. Association of sepsis-related mortality with early increase of TIMP-1/MMP-9 ratio.PLoS One. 2014; 9e94318Crossref PubMed Scopus (45) Google Scholar, 2Nukarinen E. Lindström O. Kuuliala K. Kylänpää L. Pettilä V. Puolakkainen P. Kuuliala A. Hämäläinen M. Moilanen E. Repo H. Hästbacka J. Association of matrix metalloproteinases -7, -8 and -9 and TIMP -1 with disease severity in acute pancreatitis. A cohort study.PLoS One. 2016; 11e0161480Crossref PubMed Scopus (13) Google Scholar, 3Eckfeld C. Häußler D. Schoeps B. Hermann C.D. Krüger A. Functional disparities within the TIMP family in cancer: Hints from molecular divergence.Cancer Metastasis Rev. 2019; 38: 469-481Crossref PubMed Scopus (22) Google Scholar). Originally described as the first natural collagenase inhibitor (4Woolley D.E. Roberts D.R. Evanson J.M. Inhibition of human collagenase activity by a small molecular weight serum protein.Biochem. Biophys. Res. Commun. 1975; 66: 747-754Crossref PubMed Scopus (57) Google Scholar), it was revealed that TIMP-1 is identical to erythroid-potentiating activity (5Docherty A.J. Lyons A. Smith B.J. Wright E.M. Stephens P.E. Harris T.J. Murphy G. Reynolds J.J. Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity.Nature. 1985; 318: 66-69Crossref PubMed Scopus (579) Google Scholar), a potent growth factor for erythroid progenitors. Subsequent studies revealed further effects of TIMP-1 on cells of the hematopoietic system, including B lymphoma cells (6Guedez L. Stetler-Stevenson W.G. Wolff L. Wang J. Fukushima P. Mansoor A. Stetler-Stevenson M. In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1.J. Clin. Invest. 1998; 102: 2002-2010Crossref PubMed Scopus (359) Google Scholar, 7Guedez L. Martinez A. Zhao S. Vivero A. Pittaluga S. Stetler-Stevenson M. Raffeld M. Stetler-Stevenson W.G. Tissue inhibitor of metalloproteinase 1 (TIMP-1) promotes plasmablastic differentiation of a Burkitt lymphoma cell line: Implications in the pathogenesis of plasmacytic/plasmablastic tumors.Blood. 2005; 105: 1660-1668Crossref PubMed Scopus (39) Google Scholar, 8Guedez L. Mansoor A. Birkedal-Hansen B. Lim M.S. Fukushima P. Venzon D. Stetler-Stevenson W.G. Stetler-Stevenson M. Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis.Blood. 2001; 97: 1796-1802Crossref PubMed Scopus (38) Google Scholar). Interestingly, many of the observed TIMP-1-mediated effects were shown to be independent of its antiproteolytic activity (6Guedez L. Stetler-Stevenson W.G. Wolff L. Wang J. Fukushima P. Mansoor A. Stetler-Stevenson M. In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1.J. Clin. Invest. 1998; 102: 2002-2010Crossref PubMed Scopus (359) Google Scholar, 9Chesler L. Golde D.W. Bersch N. Johnson M.D. Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1.Blood. 1995; 86: 4506-4515Crossref PubMed Google Scholar), which so far was the only major function exhibited by the N-terminal domain (10Murphy G. Houbrechts A. Cockett M.I. Williamson R.A. O’Shea M. Docherty A.J.P. The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity.Biochemistry. 1991; 30: 8097-8102Crossref PubMed Scopus (281) Google Scholar). Several years later, it was discovered that C-terminal domain–mediated interaction of TIMP-1 with the tetraspanin CD63 (11Jung K.-K. Liu X.-W. Chirco R. Fridman R. Kim H.-R.C. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein.EMBO J. 2006; 25: 3934-3942Crossref PubMed Scopus (224) Google Scholar, 12Warner R.B. Najy A.J. Jung Y.S. Fridman R. Kim S. Kim H.-R.C. Establishment of structure-function relationship of tissue inhibitor of metalloproteinase-1 for its interaction with CD63: Implication for cancer therapy.Sci. Rep. 2020; 10: 2099Crossref PubMed Scopus (8) Google Scholar) induces proteolysis-independent cytokinic signaling resulting in a variety of protumorigenic, prometastatic, and proinflammatory effects (13Cui H. Seubert B. Stahl E. Dietz H. Reuning U. Moreno-Leon L. Ilie M. Hofman P. Nagase H. Mari B. Krüger A. Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes.Oncogene. 2015; 34: 3640-3650Crossref PubMed Scopus (123) Google Scholar, 14Grünwald B. Harant V. Schaten S. Frühschütz M. Spallek R. Höchst B. Stutzer K. Berchtold S. Erkan M. Prokopchuk O. Martignoni M. Esposito I. Heikenwalder M. Gupta A. Siveke J. et al.Pancreatic pre-malignant lesions secrete TIMP1, which activates hepatic stellate cells via CD63 signaling to create a pre-metastatic niche in the liver.Gastroenterology. 2016; 151: 1011-1024Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 15Kobuch J. Cui H. Grünwald B. Saftig P. Knolle P.A. Krüger A. TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice.Haematologica. 2015; 100: 1005-1013PubMed Google Scholar, 16Schoeps B. Eckfeld C. Prokopchuk O. Böttcher J. Häußler D. Steiger K. Demir I.E. Knolle P. Soehnlein O. Jenne D.E. Hermann C.D. Krüger A. TIMP1 triggers neutrophil extracellular trap formation in pancreatic cancer.Cancer Res. 2021; 81: 3568-3579Crossref PubMed Scopus (11) Google Scholar). Hence, the multifunctionality of TIMP-1 was attributed to the existence of two physically distinct domains, the N-terminal domain mediating antiproteolytic activity as well as the C-terminal domain mediating signaling activity via CD63 (17Grünwald B. Schoeps B. Krüger A. Recognizing the molecular multifunctionality and interactome of TIMP-1.Trends Cell Biol. 2019; 29: 6-19Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). In an abstract for a symposium, without provision of experimental data (18Moreira J.M. Høeberg M. Ulrik Lademann U. Viuff B. Jensen L.V. Stenvang J. Nygård S.B. Ørum-Madsen M.S. Vistesen M.V. Fuglsang A.T. Liu S. Brünner N. Identification and characterization of a new TIMP-1 binding protein [abstract].Cancer Res. 2015; 75 (Abstract nr P5-07-08)Google Scholar), it was suggested that invariant chain (CD74) may be a possible interaction partner of TIMP-1. CD74 is, like TIMP-1, associated with inflammatory diseases (19Farr L. Ghosh S. Moonah S. Role of MIF cytokine/CD74 receptor pathway in protecting against injury and promoting repair.Front. Immunol. 2020; 11: 1273Crossref PubMed Scopus (22) Google Scholar) and is discussed as a therapeutic target in cancer (20Stein R. Mattes M.J. Cardillo T.M. Hansen H.J. Chang C.-H. Burton J. Govindan S. Goldenberg D.M. CD74: A new candidate target for the immunotherapy of B-cell neoplasms.Clin. Cancer Res. 2007; 13: 5556s-5563sCrossref PubMed Scopus (164) Google Scholar) and autoimmune diseases (21Borghese F. Clanchy F.I.L. CD74: An emerging opportunity as a therapeutic target in cancer and autoimmune disease.Expert Opin. Ther. Targets. 2011; 15: 237-251Crossref PubMed Scopus (97) Google Scholar) and notably also in the ongoing SARS-CoV-2 pandemic (22Vandenbark A.A. Meza-Romero R. Offner H. Surviving the storm: Dealing with COVID-19.Cell. Immunol. 2020; 354: 104153Crossref PubMed Scopus (3) Google Scholar). CD74 plays an essential role in many biological processes (23Schröder B. The multifaceted roles of the invariant chain CD74--more than just a chaperone.Biochim. Biophys. Acta. 2016; 1863: 1269-1281Crossref PubMed Scopus (91) Google Scholar), including antigen presentation (24Stockinger B. Pessara U. Lin R.H. Habicht J. Grez M. Koch N. A role of la-associated invariant chains in antigen processing and pressentation.Cell. 1989; 56: 683-689Abstract Full Text PDF PubMed Scopus (148) Google Scholar) and B cell development (25Shachar I. Flavell R.A. Requirement for invariant chain in B cell maturation and function.Science. 1996; 274: 106-108Crossref PubMed Scopus (107) Google Scholar). Homotrimers of CD74 bind major histocompatibility complex (MHC) class II complexes to assist their assembly and subcellular localization (23Schröder B. The multifaceted roles of the invariant chain CD74--more than just a chaperone.Biochim. Biophys. Acta. 2016; 1863: 1269-1281Crossref PubMed Scopus (91) Google Scholar, 26Roche P.A. Marks M.S. Cresswell P. Formation of a nine-subunit complex by HLA class II glycoproteins and the invariant chain.Nature. 1991; 354: 392-394Crossref PubMed Scopus (282) Google Scholar). In addition, MHC-free CD74 can also be found on the surface of immune cells (23Schröder B. The multifaceted roles of the invariant chain CD74--more than just a chaperone.Biochim. Biophys. Acta. 2016; 1863: 1269-1281Crossref PubMed Scopus (91) Google Scholar, 27Koch N. Koch S. Hämmerling G.J. Ia invariant chain detected on lymphocyte surfaces by monoclonal antibody.Nature. 1982; 299: 644-645Crossref PubMed Scopus (122) Google Scholar), where it serves as the receptor for the cytokine macrophage migration inhibitory factor (MIF) (28Leng L. Metz C.N. Fang Y. Xu J. Donnelly S. Baugh J. Delohery T. Chen Y. Mitchell R.A. Bucala R. MIF signal transduction initiated by binding to CD74.J. Exp. Med. 2003; 197: 1467-1476Crossref PubMed Scopus (789) Google Scholar). Functionally, the MIF–CD74 interaction was shown to induce intracellular zeta chain–associated protein kinase-70 (ZAP-70) signaling in B lymphoma cells (29Klasen C. Ohl K. Sternkopf M. Shachar I. Schmitz C. Heussen N. Hobeika E. Levit-Zerdoun E. Tenbrock K. Reth M. Bernhagen J. El Bounkari O. MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling.J. Immunol. 2014; 192: 5273-5284Crossref PubMed Scopus (68) Google Scholar). In the present study, we identified CD74 as a functionally active receptor for TIMP-1, mediating cytokinic signaling activity of TIMP-1. Furthermore, we identified the antiproteolytic N-terminal domain of TIMP-1 to be a functional cytokinic interaction site as well. To investigate a possible TIMP-1–CD74-interaction, we overexpressed CD74 in the human LX-2 cell line, which resulted in highly increased RNA (Fig. 1A), total protein (Fig. 1B), as well as surface protein (Fig. 1C) levels of CD74. Physical interaction between TIMP-1 and CD74 could be demonstrated by coimmunoprecipitation using the crude lysate of CD74-overexpressing cells (Fig. 1D). Furthermore, colocalization of fluorescently labeled TIMP-1 with CD74 was observed (Fig. 1E). Altogether, these data show that TIMP-1 binds to CD74. To shed light on possible interaction sites involved in TIMP-1–CD74 binding, we performed in silico molecular docking using the Haddock algorithm (30van Zundert G.C.P. Rodrigues J.P.G.L.M. Trellet M. Schmitz C. Kastritis P.L. Karaca E. Melquiond A.S.J. van Dijk M. de Vries S.J. Bonvin A.M.J.J. The HADDOCK2.2 web server: User-friendly integrative modeling of biomolecular complexes.J. Mol. Biol. 2016; 428: 720-725Crossref PubMed Scopus (1120) Google Scholar), which predicts the most likely conformation of two interacting molecules (Fig. 2A). For this, we used the full-length crystal structure of TIMP-1 (PDB ID: 1uea) (31Gomis-Rüth F.X. Maskos K. Betz M. Bergner A. Huber R. Suzuki K. Yoshida N. Nagase H. Brew K. Bourenkov G.P. Bartunik H. Bode W. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1.Nature. 1997; 389: 77-81Crossref PubMed Scopus (503) Google Scholar) and the trimerized extracellular domain of CD74 (PDB ID: 1iie) (32Jasanoff A. Wagner G. Wiley D.C. Structure of a trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii.EMBO J. 1998; 17: 6812-6818Crossref PubMed Scopus (74) Google Scholar). Of 10,000 randomly assigned interactions between TIMP-1 and CD74, the 200 energetically most favorable interactions were further refined by semiflexible annealing. The structures of these refined TIMP-1–CD74 complexes were compared and complexes with similar orientation were clustered. Of the resulting 22 clusters, the three, in respect to energetic considerations, best-ranked clusters (clusters 2, 8, and 13 (Table S1)) were further analyzed. To gain more insight in the binding sites that are involved in TIMP-1–CD74 interaction, we visualized a representative complex structure for each cluster (complex 2, complex 8, and complex 13) (Fig. 2B) and used the SpotOn algorithm, which identifies and classifies interfacial residues of protein–protein interactions (33Melo R. Fieldhouse R. Melo A. Correia J.D.G. Cordeiro M.N.D.S. Gümüş Z.H. Costa J. Bonvin A.M.J.J. Moreira I.S. A machine learning approach for hot-spot detection at protein-protein interfaces.Int. J. Mol. Sci. 2016; 17: 1215Crossref Scopus (36) Google Scholar, 34Moreira I.S. Koukos P.I. Melo R. Almeida J.G. Preto A.J. Schaarschmidt J. Trellet M. Gümüş Z.H. Costa J. Bonvin A.M.J.J. SpotOn: High accuracy identification of protein-protein interface hot-spots.Sci. Rep. 2017; 7: 8007Crossref PubMed Scopus (53) Google Scholar). This analysis revealed that, in complexes 8 and 13, TIMP-1 would interact with CD74 mainly via its N-terminal domain (Fig. 2B), including the wedge-shaped ridge at the N terminus of TIMP-1 (Fig. 2C and Fig. S1A). This interaction was predicted to involve all three monomers of the CD74 homotrimer (Fig. 2D and Fig. S1B). In contrast, complex 2 suggested binding to CD74 only via the C-terminal domain of TIMP-1 (Fig. 2, B and C and Fig. S1A). Interestingly, some of the suggested residues on CD74 that participate in the interaction with TIMP-1 (highlighted in Fig. S1B) were previously also predicted to be involved in binding of the MIF to CD74 (35Meza-Romero R. Benedek G. Leng L. Bucala R. Vandenbark A.A. Predicted structure of MIF/CD74 and RTL1000/CD74 complexes.Metab. Brain Dis. 2016; 31: 249-255Crossref PubMed Scopus (24) Google Scholar). The in silico analysis suggested two possible binding orientations of TIMP-1 to CD74. First, binding to CD74 would be mediated via the N-terminal domain of TIMP-1 (complex 8 and complex 13). Second, the interaction with CD74 would be mediated via the C-terminal domain of TIMP-1 (complex 2). To experimentally validate one of the proposed binding mechanisms, we deleted the C-terminal domain of TIMP-1 and used the purified N-terminal domain (N-TIMP-1) for in vitro studies. Confocal microscopy revealed that N-TIMP-1, similar to full-length TIMP-1 (Fig. 1B), colocalized with CD74 (Fig. 3A). This experimental approach demonstrates that the N-terminal domain of TIMP-1 is sufficient to bind to CD74, supporting the binding mechanism suggested by complexes 8 and 13. As a proof of concept, we aimed to investigate whether the identified TIMP-1–CD74 interaction also occurs in cells with natural expression of CD74. Analysis of published RNA-Seq data derived from the human protein atlas (36Uhlén M. Fagerberg L. Hallström B.M. Lindskog C. Oksvold P. Mardinoglu A. Sivertsson Å. Kampf C. Sjöstedt E. Asplund A. Olsson I. Edlund K. Lundberg E. Navani S. Szigyarto C.A.-K. et al.Proteomics. Tissue-based map of the human proteome.Science. 2015; 347: 1260419Crossref PubMed Scopus (6478) Google Scholar) revealed that cells in the immune cell compartment, particularly B cells, highly expressed CD74 (Fig. S2). Therefore, we used the Namalwa human B lymphoma cell line, which highly expressed CD74 (Fig. S3A), for further studies on TIMP-1–CD74 interactions. Dot blot binding assays using cell lysates of Namalwa cells revealed, in comparison with the negative control BSA, markedly increased binding of CD74 to immobilized recombinant TIMP-1 to a similar extent as the positive control recombinant MIF (Fig. 3B). This increase was totally abolished when TIMP-1-coated dots were incubated with lysates from CD74 knockdown cells (Fig. 3B and Fig. S3, B and C). Furthermore, colocalization of fluorescently labeled TIMP-1 and CD74 in intact Namalwa cells was observed using confocal microscopy (Fig. 3C). Importantly, N-TIMP-1 was sufficient to bind to Namalwa-derived CD74 (Fig. 3D). Next, we examined whether the identified TIMP-1–CD74 interaction is functional. For this, we analyzed phosphorylation of ZAP-70, a known downstream effector of CD74 signaling in B lymphoma cells upon binding of MIF (29Klasen C. Ohl K. Sternkopf M. Shachar I. Schmitz C. Heussen N. Hobeika E. Levit-Zerdoun E. Tenbrock K. Reth M. Bernhagen J. El Bounkari O. MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling.J. Immunol. 2014; 192: 5273-5284Crossref PubMed Scopus (68) Google Scholar). Stimulation of Namalwa cells with recombinant TIMP-1 triggered ZAP-70 phosphorylation (Fig. 4A). Importantly, TIMP-1-mediated ZAP-70 phosphorylation was dependent on CD74 because shRNAi-mediated knockdown of CD74 (Fig. 4B) completely abolished this effect (Fig. 4C). Of note, GAPDH and total ZAP-70 levels were not affected by TIMP-1 stimulation (Fig. S4). To further analyze the relevance of the above-identified interfacial residues of TIMP-1–CD74 interaction, we stimulated Namalwa cells with N-TIMP-1 and observed that the N-terminal domain was sufficient to trigger ZAP-70 phosphorylation (Fig. 4D). The abovementioned complexes 8 and 13, which were identified to reflect the most probable binding mechanism, predicted a TIMP-1-binding region on CD74 that is similar to the previously published binding region of MIF on CD74 (35Meza-Romero R. Benedek G. Leng L. Bucala R. Vandenbark A.A. Predicted structure of MIF/CD74 and RTL1000/CD74 complexes.Metab. Brain Dis. 2016; 31: 249-255Crossref PubMed Scopus (24) Google Scholar). Because MIF–CD74 interaction can be blocked with the synthetic CD74-binding peptide C36L1 occupying this binding region on CD74 (37Figueiredo C.R. Azevedo R.A. Mousdell S. Resende-Lara P.T. Ireland L. Santos A. Girola N. Cunha R.L.O.R. Schmid M.C. Polonelli L. Travassos L.R. Mielgo A. Blockade of MIF-CD74 signalling on macrophages and dendritic cells restores the antitumour immune response against metastatic melanoma.Front. Immunol. 2018; 9: 1132Crossref PubMed Scopus (49) Google Scholar), we used C36L1 to test for the plausibility of the in silico–revealed TIMP-1-interaction regions on CD74. Indeed, preincubation of cells with this peptide abolished TIMP-1–CD74-mediated ZAP-70 phosphorylation (Fig. 4E), indicating that the known cytokine-binding site on CD74 is involved in TIMP-1–CD74 interaction. Of note, we could exclude effects of the peptide on cell viability during the time frame of the experiment (Fig. S5). In this study, we identified CD74 as the functional receptor of TIMP-1. Interaction of TIMP-1 with CD74 was observed in lysates derived from cells of different origins, namely CD74-overexpressing hepatic stellate cells as well as Namalwa B lymphoma cells with natural expression of CD74. This finding was further supported by confocal microscopy revealing that fluorescently labeled exogenous TIMP-1 binds to the receptor CD74. The observation that not all TIMP-1 molecules colocalized with CD74 in cells points at additional TIMP-1-binding proteins. Indeed, several cell surface proteins are known to bind TIMP-1, including CD63 (11Jung K.-K. Liu X.-W. Chirco R. Fridman R. Kim H.-R.C. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein.EMBO J. 2006; 25: 3934-3942Crossref PubMed Scopus (224) Google Scholar), LRP-1 (38Thevenard J. Verzeaux L. Devy J. Etique N. Jeanne A. Schneider C. Hachet C. Ferracci G. David M. Martiny L. Charpentier E. Khrestchatisky M. Rivera S. Dedieu S. Emonard H. Low-density lipoprotein receptor-related protein-1 mediates endocytic clearance of tissue inhibitor of metalloproteinases-1 and promotes its cytokine-like activities.PLoS One. 2014; 9e103839Crossref PubMed Scopus (26) Google Scholar, 39Verzeaux L. Belloy N. Thevenard-Devy J. Devy J. Ferracci G. Martiny L. Dedieu S. Dauchez M. Emonard H. Etique N. Devarenne-Charpentier E. Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons.Sci. Rep. 2017; 7: 5375Crossref PubMed Scopus (6) Google Scholar), and ADAM10 (40Rapti M. Atkinson S.J. Lee M.H. Trim A. Moss M. Murphy G. The isolated N-terminal domains of TIMP-1 and TIMP-3 are insufficient for ADAM10 inhibition.Biochem. J. 2008; 411: 433-439Crossref PubMed Scopus (35) Google Scholar). Further molecular analyses on the identified interaction between TIMP-1 and CD74 led to the observation that TIMP-1 interacts with CD74 via its N-terminal domain because N-TIMP-1 alone was sufficient to bind to CD74 as well as trigger ZAP-70 activation. Still, molecular docking analyses indicated that some amino acids located in the C-terminal domain facing the wedge-shaped ridge of TIMP-1 (41Murphy G. Tissue inhibitors of metalloproteinases.Genome Biol. 2011; 12: 233Crossref PubMed Scopus (299) Google Scholar) possibly participate in the interaction with CD74 as well. Therefore, it is possible that these residues can be involved in modulation of the TIMP-1–CD74 interaction. Such contribution of amino acids of the C-terminal domain to the binding of TIMP-1 to other known N-terminal interaction partners has already been described in the context of its antiproteolytic activity because residues in the C-terminal domain are not decisive for, but involved in, fine-tuning of TIMP-1–metalloproteinase interactions (42Raeeszadeh-Sarmazdeh M. Greene K.A. Sankaran B. Downey G.P. Radisky D.C. Radisky E.S. Directed evolution of the metalloproteinase inhibitor TIMP-1 reveals that its N- and C-terminal domains cooperate in matrix metalloproteinase recognition.J. Biol. Chem. 2019; 294: 9476-9488Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 43Huang W. Suzuki K. Nagase H. Arumugan S. van Doren S.R. Brew K. Folding and characterization of the amino-terminal domain of human tissue inhibitor of metalloproteinases-1 (TIMP-1) expressed at high yield in E. coli.FEBS Lett. 1996; 384: 155-161Crossref PubMed Scopus (97) Google Scholar). TIMP-1 is a multifunctional protein with versatile impact on cellular processes. Its functions result from its two-domain structure harboring metalloproteinase inhibitory as well as cytokine activities (17Grünwald B. Schoeps B. Krüger A. Recognizing the molecular multifunctionality and interactome of TIMP-1.Trends Cell Biol. 2019; 29: 6-19Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). So far, the N-terminal domain of TIMP-1 was almost entirely recognized to be responsible for the antiproteolytic function (10Murphy G. Houbrechts A. Cockett M.I. Williamson R.A. O’Shea M. Docherty A.J.P. The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity.Biochemistry. 1991; 30: 8097-8102Crossref PubMed Scopus (281) Google Scholar), while it emerged that the C-terminal domain is the mediator of its cytokinic activity (11Jung K.-K. Liu X.-W. Chirco R. Fridman R. Kim H.-R.C. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein.EMBO J. 2006; 25: 3934-3942Crossref PubMed Scopus (224) Google Scholar, 12Warner R.B. Najy A.J. Jung Y.S. Fridman R. Kim S. Kim H.-R.C. Establishment of structure-function relationship of tissue inhibitor of metalloproteinase-1 for its interaction with CD63: Implication for cancer therapy.Sci. Rep. 2020; 10: 2099Crossref PubMed Scopus (8) Google Scholar). This appreciation now has to be revised as we here demonstrate that the N-terminal domain of TIMP-1 binds to CD74 and triggers ZAP-70 activation in Namalwa B lymphoma cells. Thus, the multifunctionality of TIMP-1 expands beyond functional separation of two distinct domains because the N-terminal domain harbors both metalloproteinase inhibitory and cytokinic functions. CD74 is, like TIMP-1, highly expressed in inflammatory conditions (19Farr L. Ghosh S. Moonah S. Role of MIF cytokine/CD74 receptor pathway in protecting against injury and promoting repair.Front. Immunol. 2020; 11: 1273Crossref PubMed Scopus (22) Google Scholar) and has been shown to be involved in a multitude of biological processes (23Schröder B. The multifaceted roles of the invariant chain CD74--more than just a chaperone.Biochim. Biophys. Acta. 2016; 1863: 1269-1281Crossref PubMed Scopus (91) Google Scholar), including antigen presentation (24Stockinger B. Pessara U. Lin R.H. Habicht J. Grez M. Koch N. A role of la-associated invariant chains in antigen processing and pressentation.Cell. 1989; 56: 683-689Abstract Full Text PDF PubMed Scopus (148) Google Scholar) and cellular signaling (29Klasen C. Ohl K. Sternkopf M. Shachar I. Schmitz C. Heussen N. Hobeika E. Levit-Zerdoun E. Tenbrock K. Reth M. Bernhagen J. El Bounkari O. MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling.J. Immunol. 2014; 192: 5273-5284Crossref PubMed Scopus (68) Google Scholar). So far, the only known ligand of CD74 was the proinflammatory cytokine MIF, and MIF–CD74 interaction was shown to induce ZAP-70 signaling in B lymphoma cells (29Klasen C. Ohl K. Sternkopf M. Shachar I. Schmitz C. Heussen N. Hobeika E. Levit-Zerdoun E. Tenbrock K. Reth M. Bernhagen J. El Bounkari O. MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling.J. Immunol. 2014; 192: 5273-5284Crossref PubMed Scopus (68) Google Scholar). The clinical relevance of ligand-induced CD74 activity is demonstrated by clinical trials using anti-CD74 antibodies for the therapy of malignant B cell lymphoma (44Martin P. Furman R.R. Rutherford S. Ruan J. Ely S. Greenberg J. Coleman M. Goldsmith S.J. Leonard J.P. Phase I study of the anti-CD74 monoclonal antibody milatuzumab (hLL1) in patients with previ" @default.
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• W3189100137 title "Identification of invariant chain CD74 as a functional receptor of tissue inhibitor of metalloproteinases-1 (TIMP-1)" @default.
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