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• W2989661513 abstract "Tyrosyl-tRNA synthetase ligates tyrosine to its cognate tRNA in the cytoplasm, but it can also be secreted through a noncanonical pathway. We found that extracellular tyrosyl-tRNA synthetase (YRS) exhibited proinflammatory activities. In addition to acting as a monocyte/macrophage chemoattractant, YRS initiated signaling through Toll-like receptor 2 (TLR2) resulting in NF-κB activation and release of tumor necrosis factor α (TNFα) and multiple chemokines, including MIP-1α/β, CXCL8 (IL8), and CXCL1 (KC) from THP1 monocyte and peripheral blood mononuclear cell–derived macrophages. Furthermore, YRS up-regulated matrix metalloproteinase (MMP) activity in a TNFα-dependent manner in M0 macrophages. Because MMPs process a variety of intracellular proteins that also exhibit extracellular moonlighting functions, we profiled 10 MMPs for YRS cleavage and identified 55 cleavage sites by amino-terminal oriented mass spectrometry of substrates (ATOMS) positional proteomics and Edman degradation. Stable proteoforms resulted from cleavages near the start of the YRS C-terminal EMAPII domain. All of the MMPs tested cleaved at ADS386↓387LYV and VSG405↓406LVQ, generating 43- and 45-kDa fragments. The highest catalytic efficiency for YRS was demonstrated by MMP7, which is highly expressed by monocytes and macrophages, and by neutrophil-specific MMP8. MMP-cleaved YRS enhanced TLR2 signaling, increased TNFα secretion from macrophages, and amplified monocyte/macrophage chemotaxis compared with unprocessed YRS. The cleavage of YRS by MMP8, but not MMP7, was inhibited by tyrosine, a substrate of the YRS aminoacylation reaction. Overall, the proinflammatory activity of YRS is enhanced by MMP cleavage, which we suggest forms a feed-forward mechanism to promote inflammation. Tyrosyl-tRNA synthetase ligates tyrosine to its cognate tRNA in the cytoplasm, but it can also be secreted through a noncanonical pathway. We found that extracellular tyrosyl-tRNA synthetase (YRS) exhibited proinflammatory activities. In addition to acting as a monocyte/macrophage chemoattractant, YRS initiated signaling through Toll-like receptor 2 (TLR2) resulting in NF-κB activation and release of tumor necrosis factor α (TNFα) and multiple chemokines, including MIP-1α/β, CXCL8 (IL8), and CXCL1 (KC) from THP1 monocyte and peripheral blood mononuclear cell–derived macrophages. Furthermore, YRS up-regulated matrix metalloproteinase (MMP) activity in a TNFα-dependent manner in M0 macrophages. Because MMPs process a variety of intracellular proteins that also exhibit extracellular moonlighting functions, we profiled 10 MMPs for YRS cleavage and identified 55 cleavage sites by amino-terminal oriented mass spectrometry of substrates (ATOMS) positional proteomics and Edman degradation. Stable proteoforms resulted from cleavages near the start of the YRS C-terminal EMAPII domain. All of the MMPs tested cleaved at ADS386↓387LYV and VSG405↓406LVQ, generating 43- and 45-kDa fragments. The highest catalytic efficiency for YRS was demonstrated by MMP7, which is highly expressed by monocytes and macrophages, and by neutrophil-specific MMP8. MMP-cleaved YRS enhanced TLR2 signaling, increased TNFα secretion from macrophages, and amplified monocyte/macrophage chemotaxis compared with unprocessed YRS. The cleavage of YRS by MMP8, but not MMP7, was inhibited by tyrosine, a substrate of the YRS aminoacylation reaction. Overall, the proinflammatory activity of YRS is enhanced by MMP cleavage, which we suggest forms a feed-forward mechanism to promote inflammation. Matrix metalloproteinases (MMPs) 6The abbreviations used are: MMPmatrix metalloproteinaseAp4AP1,P4-di(adenosine-5′) tetraphosphateAp5AP1,P5-di(adenosine-5′) pentaphosphateAPMAp-aminophenylmercuric acetateATOMSamino-terminal oriented mass spectrometry of substratesCCLCC chemokine ligandCCScosmic calf serumEMAPIIendothelial monocyte-activating polypeptide IIIFNinterferonILinterleukiniTRAQisobaric tags for relative and absolute quantificationLPSlipopolysaccharidePARP-1poly(ADP-ribose) polymerase 1PBMCperipheral blood mononuclear cellPMAphorbol 12-myristate 13-acetateRPMIRoswell Park Memorial InstituteTAILSterminal amine isotopic labeling of substratesTLRtoll-like receptorTNFtumor necrosis factorWRStryptophanyl-tRNA synthetaseYRStyrosyl-tRNA synthetasePDBProtein Data BankELISAenzyme-linked immunosorbent assayANOVAanalysis of variancePVDFpolyvinylidene difluoride. are a family of 23 secreted and membrane-anchored proteases (1Parks W.C. Wilson C.L. López-Boado Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity.Nat. Rev. Immunol. 2004; 4 (15286728): 617-62910.1038/nri1418Crossref PubMed Scopus (1426) Google Scholar). By cleaving a variety of signaling molecules in addition to extracellular matrix components (2Rodríguez D. Morrison C.J. Overall C.M. Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics.Biochim. Biophys. Acta. 2010; 1803 (19800373): 39-5410.1016/j.bbamcr.2009.09.015Crossref PubMed Scopus (411) Google Scholar), MMPs regulate many different processes, including inflammation (1Parks W.C. Wilson C.L. López-Boado Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity.Nat. Rev. Immunol. 2004; 4 (15286728): 617-62910.1038/nri1418Crossref PubMed Scopus (1426) Google Scholar, 2Rodríguez D. Morrison C.J. Overall C.M. Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics.Biochim. Biophys. Acta. 2010; 1803 (19800373): 39-5410.1016/j.bbamcr.2009.09.015Crossref PubMed Scopus (411) Google Scholar, 3McQuibban G.A. Gong J.H. Tam E.M. McCulloch C.A. Clark-Lewis I. Overall C.M. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3.Science. 2000; 289 (10947989): 1202-120610.1126/science.289.5482.1202Crossref PubMed Scopus (631) Google Scholar, 4Butler G.S. Overall C.M. Updated biological roles for matrix metalloproteinases and new “Intracellular” substrates revealed by degradomics.Biochemistry. 2009; 48 (19817485): 10830-1084510.1021/bi901656fCrossref PubMed Scopus (177) Google Scholar, 5Jobin P.G. Butler G.S. Overall C.M. New intracellular activities of matrix metalloproteinases shine in the moonlight.Biochim. Biophys. Acta Mol. Cell Res. 2017; 1864 (28526562): 2043-205510.1016/j.bbamcr.2017.05.013Crossref PubMed Scopus (91) Google Scholar, 6Bellac C.L. Dufour A. Krisinger M.J. Loonchanta A. Starr A.E. Auf dem Keller U. Lange P.F. Goebeler V. Kappelhoff R. Butler G.S. Burtnick L.D. Conway E.M. Roberts C.R. Overall C.M. Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis.Cell Rep. 2014; 9 (25310974): 618-63210.1016/j.celrep.2014.09.006Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 7Dufour A. Bellac C.L. Eckhard U. Solis N. Klein T. Kappelhoff R. Fortelny N. Jobin P. Rozmus J. Mark J. Pavlidis P. Dive V. Barbour S.J. Overall C.M. C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease.Nat. Commun. 2018; 9 (29925830): 241610.1038/s41467-018-04717-4Crossref PubMed Scopus (31) Google Scholar). Notably, the innate immune cell MMPs, neutrophil-specific MMP8 (8Tester A.M. Cox J.H. Connor A.R. Starr A.E. Dean R.A. Puente X.S. López-Otín C. Overall C.M. LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity.PLoS ONE. 2007; 2 (17375198): e31210.1371/journal.pone.0000312Crossref PubMed Scopus (171) Google Scholar) and monocyte/macrophage-lineage MMP7 (9Wilson C.L. Ouellette A.J. Satchell D.P. Ayabe T. López-Boado Y.S. Stratman J.L. Hultgren S.J. Matrisian L.M. Parks W.C. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense.Science. 1999; 286 (10506557): 113-11710.1126/science.286.5437.113Crossref PubMed Scopus (894) Google Scholar) and MMP12 (14Cox J.H. Starr A.E. Kappelhoff R. Yan R. Roberts C.R. Overall C.M. Matrix metalloproteinase 8 deficiency in mice exacerbates inflammatory arthritis through delayed neutrophil apoptosis and reduced caspase 11 expression.Arthritis Rheum. 2010; 62 (21120997): 3645-365510.1002/art.27757Crossref PubMed Scopus (49) Google Scholar), orchestrate leukocyte chemotaxis during inflammation by activating and inactivating cleavages of chemokines. Indeed, the majority of human CC chemokine ligands (CCL) that regulate monocyte and macrophage chemotaxis and activation are cleaved by these and other MMPs (3McQuibban G.A. Gong J.H. Tam E.M. McCulloch C.A. Clark-Lewis I. Overall C.M. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3.Science. 2000; 289 (10947989): 1202-120610.1126/science.289.5482.1202Crossref PubMed Scopus (631) Google Scholar, 12McQuibban G.A. Gong J.-H. Wong J.P. Wallace J.L. Clark-Lewis I. Overall C.M. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo.Blood. 2002; 100 (12149192): 1160-116710.1182/blood.V100.4.1160.h81602001160_1160_1167Crossref PubMed Google Scholar, 13Starr A.E. Dufour A. Maier J. Overall C.M. Biochemical analysis of matrix metalloproteinase activation of chemokines CCL15 and CCL23 and increased glycosaminoglycan binding of CCL16.J. Biol. Chem. 2012; 287 (22147696): 5848-586010.1074/jbc.M111.314609Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), as are all seven human ELR+ CXCL neutrophil chemokines, including CXCL8 (IL8). For CCL chemokines, inactivation or generation of antagonists by MMPs are common sequelae, whereas CXCL activation by neutrophil MMP8 is followed later by inactivating cleavages just C-terminal to or within the ELR motif by MMP12 (11Dean R.A. Cox J.H. Bellac C.L. Doucet A. Starr A.E. Overall C.M. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx.Blood. 2008; 112 (18660381): 3455-346410.1182/blood-2007-12-129080Crossref PubMed Scopus (182) Google Scholar), which temporally regulates neutrophil chemoattraction in vivo (6Bellac C.L. Dufour A. Krisinger M.J. Loonchanta A. Starr A.E. Auf dem Keller U. Lange P.F. Goebeler V. Kappelhoff R. Butler G.S. Burtnick L.D. Conway E.M. Roberts C.R. Overall C.M. Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis.Cell Rep. 2014; 9 (25310974): 618-63210.1016/j.celrep.2014.09.006Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 8Tester A.M. Cox J.H. Connor A.R. Starr A.E. Dean R.A. Puente X.S. López-Otín C. Overall C.M. LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity.PLoS ONE. 2007; 2 (17375198): e31210.1371/journal.pone.0000312Crossref PubMed Scopus (171) Google Scholar, 11Dean R.A. Cox J.H. Bellac C.L. Doucet A. Starr A.E. Overall C.M. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx.Blood. 2008; 112 (18660381): 3455-346410.1182/blood-2007-12-129080Crossref PubMed Scopus (182) Google Scholar, 14Cox J.H. Starr A.E. Kappelhoff R. Yan R. Roberts C.R. Overall C.M. Matrix metalloproteinase 8 deficiency in mice exacerbates inflammatory arthritis through delayed neutrophil apoptosis and reduced caspase 11 expression.Arthritis Rheum. 2010; 62 (21120997): 3645-365510.1002/art.27757Crossref PubMed Scopus (49) Google Scholar). Cytokines such as interferon (IFN) α (10Marchant D.J. Bellac C.L. Moraes T.J. Wadsworth S.J. Dufour A. Butler G.S. Bilawchuk L.M. Hendry R.G. Robertson A.G. Cheung C.T. Ng J. Ang L. Luo Z. Heilbron K. Norris M.J. et al.A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity.Nat. Med. 2014; 20 (24784232): 493-50210.1038/nm.3508Crossref PubMed Scopus (174) Google Scholar) and IFNγ (7Dufour A. Bellac C.L. Eckhard U. Solis N. Klein T. Kappelhoff R. Fortelny N. Jobin P. Rozmus J. Mark J. Pavlidis P. Dive V. Barbour S.J. Overall C.M. C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease.Nat. Commun. 2018; 9 (29925830): 241610.1038/s41467-018-04717-4Crossref PubMed Scopus (31) Google Scholar) and complement proteins, including mannose-binding lectin (15Butler G.S. Sim D. Tam E. Devine D. Overall C.M. Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolysis: potential role in human MBL deficiency.J. Biol. Chem. 2002; 277 (11891230): 17511-1751910.1074/jbc.M201461200Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar), C1q (16Ruiz S. Henschen-Edman A.H. Nagase H. Tenner A.J. Digestion of C1q collagen-like domain with MMPs-1, -2, -3, and -9 further defines the sequence involved in the stimulation of neutrophil superoxide production.J. Leukoc. Biol. 1999; 66 (10496311): 416-42210.1002/jlb.66.3.416Crossref PubMed Scopus (27) Google Scholar), C3, C3a, C3b, and C5a (6Bellac C.L. Dufour A. Krisinger M.J. Loonchanta A. Starr A.E. Auf dem Keller U. Lange P.F. Goebeler V. Kappelhoff R. Butler G.S. Burtnick L.D. Conway E.M. Roberts C.R. Overall C.M. Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis.Cell Rep. 2014; 9 (25310974): 618-63210.1016/j.celrep.2014.09.006Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), are also MMP substrates in vivo. Thus, MMP processing of these bioactive substrates dampens inflammation with MMPs playing beneficial roles essential for terminating inflammatory responses (3McQuibban G.A. Gong J.H. Tam E.M. McCulloch C.A. Clark-Lewis I. Overall C.M. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3.Science. 2000; 289 (10947989): 1202-120610.1126/science.289.5482.1202Crossref PubMed Scopus (631) Google Scholar, 17Dufour A. Overall C.M. Missing the target: matrix metalloproteinase antitargets in inflammation and cancer.Trends Pharmacol. 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