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Histaminylation of fibrinogen by tissue transglutaminase-2 (TGM-2): potential role in modulating inflammation

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Abstract

Plasma fibrinogen plays an important role in hemostasis and inflammation. Fibrinogen is converted to fibrin to impede blood loss and serves as the provisional matrix that aids wound healing. Fibrinogen also binds to cytokine activated endothelial cells and promotes the binding and migration of leukocytes into tissues during inflammation. Tissue transglutaminase (TGM-2) released from injured cells could cross-link fibrinogen to form multivalent complexes that could promote adhesion of platelets and vascular cells to endothelium. Histamine released by mast cells is a potent biogenic amine that promotes inflammation. The covalent attachment of histamine to proteins (histaminylation) by TGM-2 could modify local inflammatory reactions. We investigated TGM-2 crosslinking of several biogenic amines (serotonin, histamine, dopamine and noradrenaline) to fibrinogen. We identified histaminylation of fibrinogen by TGM-2 as a preferred reaction in solid and solution phase transglutaminase assays. Histamine caused a concentration-dependent inhibition of fibrinogen cross-linking by TGM-2. Fibrinogen that was not TGM-2 crosslinked bound to un-activated endothelial cells with low affinity. However, the binding was increased by sevenfold when fibrinogen was cross-linked by TGM-2. Histaminylation of fibrinogen also inhibited TGM-2 crosslinking of fibrinogen and the binding to un-activated HUVEC cells by 75–90 %. In summary, the histaminylation of fibrinogen by TGM-2 could play a role in modifying inflammation by sequestering free histamine and by inhibiting TGM-2 crosslinking of fibrinogen.

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References

  • Altieri DC, Plescia J et al (1993) The structural motif glycine 190-valine 202 of the fibrinogen gamma chain interacts with CD11b/CD18 integrin (alpha M beta 2, Mac-1) and promotes leukocyte adhesion. J Biol Chem 268(3):1847–1853

    PubMed  CAS  Google Scholar 

  • Ariens RA, Lai TS et al (2002) Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 100(3):743–754

    Article  PubMed  CAS  Google Scholar 

  • Barsigian C, Stern AM et al (1991) Tissue (type II) transglutaminase covalently incorporates itself, fibrinogen, or fibronectin into high molecular weight complexes on the extracellular surface of isolated hepatocytes. Use of 2-[(2-oxopropyl)thio] imidazolium derivatives as cellular transglutaminase inactivators. J Biol Chem 266(33):22501–22509

    PubMed  CAS  Google Scholar 

  • Belkin AM, Tsurupa G et al (2005) Transglutaminase-mediated oligomerization of the fibrin(ogen) alphaC domains promotes integrin-dependent cell adhesion and signaling. Blood 105(9):3561–3568

    Article  PubMed  CAS  Google Scholar 

  • Cardinali M, Uchino R et al (1990) Interaction of fibrinogen with murine melanoma cells: covalent association with cell membranes and protection against recognition by lymphokine-activated killer cells. Cancer Res 50(24):8010–8016

    PubMed  CAS  Google Scholar 

  • Dale GL, Friese P et al (2002) Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Nature 415(6868):175–179

    Article  PubMed  CAS  Google Scholar 

  • Davalos D, Akassoglou K (2012) Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34(1):43–62

    Article  PubMed  CAS  Google Scholar 

  • Duperray A, Languino LR et al (1997) Molecular identification of a novel fibrinogen binding site on the first domain of ICAM-1 regulating leukocyte-endothelium bridging. J Biol Chem 272(1):435–441

    Article  PubMed  CAS  Google Scholar 

  • Fesus L, Szucs EF et al (1985) Activation of transglutaminase and production of protein-bound gamma-glutamylhistamine in stimulated mouse mast cells. J Biol Chem 260(25):13771–13778

    PubMed  CAS  Google Scholar 

  • Greenberg CS, Birckbichler PJ et al (1991) Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J 5(15):3071–3077

    PubMed  CAS  Google Scholar 

  • Hao F, Tan M et al (2008) Histamine induces Egr-1 expression in human aortic endothelial cells via the H1 receptor-mediated protein kinase Cdelta-dependent ERK activation pathway. J Biol Chem 283(40):26928–26936

    Article  PubMed  CAS  Google Scholar 

  • Kimura S, Wang KY et al (2004) Acute inflammatory reactions caused by histamine via monocytes/macrophages chronically participate in the initiation and progression of atherosclerosis. Pathol Int 54(7):465–474

    Article  PubMed  CAS  Google Scholar 

  • Lai TS, Achyuthan KE et al (1994) Carboxyl-terminal truncation of recombinant factor XIII A-chains. Characterization of minimum structural requirement for transglutaminase activity. J Biol Chem 269(40):24596–24601

    PubMed  CAS  Google Scholar 

  • Lai TS, Slaughter TF et al (1998) Regulation of human tissue transglutaminase function by magnesium- nucleotide complexes. Identification of distinct binding sites for Mg- GTP and Mg-ATP. J Biol Chem 273(3):1776–1781

    Article  PubMed  CAS  Google Scholar 

  • Lai TS, Liu Y et al (2007) Identification of two GTP-independent alternatively spliced forms of tissue transglutaminase in human leukocytes, vascular smooth muscle, and endothelial cells. FASEB J 21(14):4131–4143

    Article  PubMed  CAS  Google Scholar 

  • Languino LR, Plescia J et al (1993) Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell 73(7):1423–1434

    Article  PubMed  CAS  Google Scholar 

  • Lentini A, Tabolacci C et al (2011) Spermidine delays eye lens opacification in vitro by suppressing transglutaminase-catalyzed crystallin cross-linking. Protein J 30(2):109–114

    Article  PubMed  CAS  Google Scholar 

  • Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4(2):140–156

    Article  PubMed  CAS  Google Scholar 

  • Lorand L, Chenoweth D et al (1972) Titration of the acceptor cross-linking sites in fibrin. Ann N Y Acad Sci 202:155–171

    Article  PubMed  CAS  Google Scholar 

  • MacCallum PK, Meade TW (1999) Haemostatic function, arterial disease and the prevention of arterial thrombosis. Baillieres Best Pract Res Clin Haematol 12(3):577–599

    Article  PubMed  CAS  Google Scholar 

  • MacGlashan D Jr (2003) Histamine: a mediator of inflammation. J Allergy Clin Immunol 112(4 Suppl):S53–S59

    Article  PubMed  CAS  Google Scholar 

  • Martinez J, Rich E et al (1989) Transglutaminase-mediated cross-linking of fibrinogen by human umbilical vein endothelial cells. J Biol Chem 264(34):20502–20508

    PubMed  CAS  Google Scholar 

  • Miraglia CC, Greenberg CS (1985) Measurement of blood coagulation Factor XIIIa formation in plasma containing glycyl-l-prolyl-l-arginyl-l-proline. Anal Biochem 144(1):165–171

    Article  PubMed  CAS  Google Scholar 

  • Murthy SN, Lorand L (1990) Cross-linked A alpha.gamma chain hybrids serve as unique markers for fibrinogen polymerized by tissue transglutaminase. Proc Natl Acad Sci USA 87(24):9679–9682

    Article  PubMed  CAS  Google Scholar 

  • Murthy SN, Wilson J et al (1991) Intramolecular crosslinking of monomeric fibrinogen by tissue transglutaminase. Proc Natl Acad Sci USA 88(23):10601–10604

    Article  PubMed  CAS  Google Scholar 

  • Pincus JH, Waelsch H (1968) The specificity of transglutaminase. II. Structural requirements of the amine substrate. Arch Biochem Biophys 126(1):44–52

    Article  PubMed  CAS  Google Scholar 

  • Prodan CI, Joseph PM et al (2007) Coated-platelet levels are influenced by smoking, aspirin, and selective serotonin reuptake inhibitors. J Thromb Haemost 5(10):2149–2151

    Article  PubMed  CAS  Google Scholar 

  • Qiao SW, Piper J et al (2005) Tissue transglutaminase-mediated formation and cleavage of histamine-gliadin complexes: biological effects and implications for celiac disease. J Immunol 174(3):1657–1663

    PubMed  CAS  Google Scholar 

  • Raveendran VV, Tan X et al (2011) Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells. Immunology 132(4):578–588

    Article  PubMed  CAS  Google Scholar 

  • Sasaguri Y, Tanimoto A (2004) Role of macrophage-derived histamine in atherosclerosis– chronic participation in the inflammatory response. J Atheroscler Thromb 11(3):122–130

    Article  PubMed  CAS  Google Scholar 

  • Shainoff JR, Urbanic DA et al (1991) Immunoelectrophoretic characterizations of the cross-linking of fibrinogen and fibrin by factor XIIIa and tissue transglutaminase. Identification of a rapid mode of hybrid alpha-/gamma-chain cross-linking that is promoted by the gamma-chain cross-linking. J Biol Chem 266(10):6429–6437

    PubMed  CAS  Google Scholar 

  • Slaughter TF, Achyuthan KE et al (1992) A microtiter plate transglutaminase assay utilizing 5-(biotinamido)pentylamine as substrate. Anal Biochem 205(1):166–171

    Article  PubMed  CAS  Google Scholar 

  • Szasz R, Dale GL (2002) Thrombospondin and fibrinogen bind serotonin-derivatized proteins on COAT-platelets. Blood 100(8):2827–2831

    Article  PubMed  CAS  Google Scholar 

  • Vowinckel J, Stahlberg S et al (2012) Histaminylation of glutamine residues is a novel posttranslational modification implicated in G-protein signaling. FEBS Lett 586(21):3819–3824

    Article  PubMed  CAS  Google Scholar 

  • Walther DJ, Peter JU et al (2003) Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell 115(7):851–862

    Article  PubMed  CAS  Google Scholar 

  • Walther DJ, Stahlberg S et al (2011) Novel roles for biogenic monoamines: from monoamines in transglutaminase-mediated post-translational protein modification to monoaminylation deregulation diseases. FEBS J 278(24):4740–4755

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank MUSC for the support. This research was funded in part by NIH grants HL072184 (CSG) and NS050541 (TSL). The technical assistance of Annemarie Nagle and Jeremy F. Freifeld is highly appreciated.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA

    Thung-S. Lai & Charles S. Greenberg

  2. The Institute of Biomedical Sciences, Mackay Medical College, No. 46, Sec. 3, Jhong-Jheng Rd., Sanzhi Dist., New Taipei City 252, Taiwan, ROC

    Thung-S. Lai

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  1. Thung-S. Lai
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  2. Charles S. Greenberg
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Correspondence to Thung-S. Lai.

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Lai, TS., Greenberg, C.S. Histaminylation of fibrinogen by tissue transglutaminase-2 (TGM-2): potential role in modulating inflammation. Amino Acids 45, 857–864 (2013). https://doi.org/10.1007/s00726-013-1532-y

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  • DOI: https://doi.org/10.1007/s00726-013-1532-y

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