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PTX3

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Template:PBB Pentraxin-related protein PTX3 also known as TNF-inducible gene 14 protein (TSG-14) is a protein that in humans is encoded by the PTX3 gene.[1][2]

Pentraxin 3 (ptx3) is a member of the pentraxin superfamily. This super family characterized by cyclic multimeric structure.[3] PTX3 is rapidly produced and released by several cell types, in particular by mononuclear phagocytes, dendritic cells (DCs), fibroblasts and endothelial cells in response to primary inflammatory signals [e.g., toll-like receptor (TLR) engagement, TNFα, IL-1β].[4] PTX3 binds with high affinity to the complement component C1q, the extracellular matrix component TNFα induced protein 6 (TNFAIP6; also called TNF-stimulated gene 6, TSG-6) and selected microorganisms, including Aspergillus fumigatus and Pseudomonas aeruginosa.[5][6][7][8][9] PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs.[4][7][5]

Structure

Human and murine PTX3, localized in the synthenic region of chromosome 3 (q24-28), are highly conserved, sharing 82% identical and 92% conserved amino acids. The human PTX3 gene is organized into three exons coding for the leader peptide (which is cleaved from the mature protein), the amino-terminal domain and the pentraxin domain of the protein.

The transcribed PTX3 protein is 381 amino acids long, has a predicted molecular weight of 40,165 Da and consists of a carboxy-terminal 203 amino acid long pentraxin domain coupled with an amino-terminal 178 amino acid long domain unrelated to other known proteins. The PTX3 carboxy-terminal domain contains a canonical pentraxin signature (HxCxS/TWxS) and two conserved cysteines (Cys-210 and Cys-271), and shares 57% conserved and 17% identical amino acids with short pentraxins. The presence of an amino-linked glycosylation site in the carboxy-terminal domain at Asn-220 accounts for the higher molecular weight observed in SDS–PAGE under reducing conditions (45 kDa as opposed to the predicted 40 kDa). Under native conditions PTX3 protomers are assembled to form multimers.[6] The crystal structure of PTX3 has not been determined yet, however according to modeling, the PTX3 pentraxin domain well-accommodates on the tertiary fold of SAP, with almost all of the β-strands and the α-helical segments conserved.[10]

PTX3 in blood

PTX3 behaves as an acute phase response protein, as the blood levels of PTX3, low in normal conditions (about 25 ng/mL in the mouse, < 2 ng/mL in humans), increase rapidly (peaking at 6–8 h after induction) and dramatically (200–800 ng/mL) during endotoxic shock, sepsis and other inflammatory and infectious conditions, correlating with the severity of the disease. Under these conditions, PTX3 is a rapid marker for primary local activation of innate immunity and inflammation.[11][12][13][14][11][15]

Pathogen versus apoptotic self recognition

Similar to other members of the pentraxin family PTX3 binds apoptotic cells, thereby inhibiting their recognition by DCs . Binding occurs late in the apoptotic process and enhances cytokine production by DCs. In addition, preincubation of apoptotic cells with PTX3 enhances C1q binding and C3 deposition on the cell surface, suggesting a role for PTX3 in the complement-mediated clearance of apoptotic cells.[16][17][18] Moreover, in the presence of dying cells, PTX3 restricts the cross presentation of antigens derived from dying cells. These results suggest that PTX3 has a dual role: protection against pathogens and control of autoimmunity.[18][19]

References

  1. ^ Breviario F; d'Aniello EM; Golay J; Peri G; Bottazzi B; Bairoch A; Saccone S; Marzella R; Predazzi V (Dec 1992). "Interleukin-1-inducible genes in endothelial cells. Cloning of a new gene related to C-reactive protein and serum amyloid P component". J Biol Chem. 267 (31): 22190–7. PMID 1429570. {{cite journal}}: Invalid |display-authors=10 (help); Unknown parameter |author-separator= ignored (help)
  2. ^ "Entrez Gene: PTX3 Pentraxin-related gene, rapidly induced by IL-1 beta".
  3. ^ Emsley J, White HE, O'Hara BP, Oliva G, Srinivasan N, Tickle IJ, Blundell TL, Pepys MB, Wood SP (January 1994). "Structure of pentameric human serum amyloid P component". Nature. 367 (6461): 338–45. doi:10.1038/367338a0. PMID 8114934.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b Garlanda C, Bottazzi B, Bastone A, Mantovani A (2005). "Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility". Annu. Rev. Immunol. 23: 337–66. doi:10.1146/annurev.immunol.23.021704.115756. PMID 15771574.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b Diniz SN, Nomizo R, Cisalpino PS, Teixeira MM, Brown GD, Mantovani A, Gordon S, Reis LF, Dias AA (April 2004). "PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages". J. Leukoc. Biol. 75 (4): 649–56. doi:10.1189/jlb.0803371. PMID 14726497.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b Bottazzi B, Vouret-Craviari V, Bastone A, De Gioia L, Matteucci C, Peri G, Spreafico F, Pausa M, D'Ettorre C, Gianazza E, Tagliabue A, Salmona M, Tedesco F, Introna M, Mantovani A (December 1997). "Multimer formation and ligand recognition by the long pentraxin PTX3. Similarities and differences with the short pentraxins C-reactive protein and serum amyloid P component". J. Biol. Chem. 272 (52): 32817–23. doi:10.1074/jbc.272.52.32817. PMID 9407058.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  7. ^ a b Garlanda C, Hirsch E, Bozza S, Salustri A, De Acetis M, Nota R, Maccagno A, Riva F, Bottazzi B, Peri G, Doni A, Vago L, Botto M, De Santis R, Carminati P, Siracusa G, Altruda F, Vecchi A, Romani L, Mantovani A (November 2002). "Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response". Nature. 420 (6912): 182–6. doi:10.1038/nature01195. PMID 12432394.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Nauta AJ, Bottazzi B, Mantovani A, Salvatori G, Kishore U, Schwaeble WJ, Gingras AR, Tzima S, Vivanco F, Egido J, Tijsma O, Hack EC, Daha MR, Roos A (February 2003). "Biochemical and functional characterization of the interaction between pentraxin 3 and C1q". Eur. J. Immunol. 33 (2): 465–73. doi:10.1002/immu.200310022. PMID 12645945.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Salustri A, Garlanda C, Hirsch E, De Acetis M, Maccagno A, Bottazzi B, Doni A, Bastone A, Mantovani G, Beck Peccoz P, Salvatori G, Mahoney DJ, Day AJ, Siracusa G, Romani L, Mantovani A (April 2004). "PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization". Development. 131 (7): 1577–86. doi:10.1242/dev.01056. PMID 14998931.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Introna M, Alles VV, Castellano M, Picardi G, De Gioia L, Bottazzai B, Peri G, Breviario F, Salmona M, De Gregorio L, Dragani TA, Srinivasan N, Blundell TL, Hamilton TA, Mantovani A (March 1996). "Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites". Blood. 87 (5): 1862–72. PMID 8634434.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b Muller B, Peri G, Doni A, Torri V, Landmann R, Bottazzi B, Mantovani A (July 2001). "Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients". Crit. Care Med. 29 (7): 1404–7. doi:10.1097/00003246-200107000-00017. PMID 11445697.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Fazzini F, Peri G, Doni A, Dell'Antonio G, Dal Cin E, Bozzolo E, D'Auria F, Praderio L, Ciboddo G, Sabbadini MG, Manfredi AA, Mantovani A, Querini PR (December 2001). "PTX3 in small-vessel vasculitides: an independent indicator of disease activity produced at sites of inflammation". Arthritis Rheum. 44 (12): 2841–50. doi:10.1002/1529-0131(200112)44:12<2841::AID-ART472>3.0.CO;2-6. PMID 11762945.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Mairuhu AT, Peri G, Setiati TE, Hack CE, Koraka P, Soemantri A, Osterhaus AD, Brandjes DP, van der Meer JW, Mantovani A, van Gorp EC (August 2005). "Elevated plasma levels of the long pentraxin, pentraxin 3, in severe dengue virus infections". J. Med. Virol. 76 (4): 547–52. doi:10.1002/jmv.20397. PMID 15977234.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Azzurri A, Sow OY, Amedei A, Bah B, Diallo S, Peri G, Benagiano M, D'Elios MM, Mantovani A, Del Prete G (January 2005). "IFN-gamma-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection". Microbes Infect. 7 (1): 1–8. doi:10.1016/j.micinf.2004.09.004. PMID 15716076.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Latini R, Maggioni AP, Peri G, Gonzini L, Lucci D, Mocarelli P, Vago L, Pasqualini F, Signorini S, Soldateschi D, Tarli L, Schweiger C, Fresco C, Cecere R, Tognoni G, Mantovani A (October 2004). "Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction". Circulation. 110 (16): 2349–54. doi:10.1161/01.CIR.0000145167.30987.2E. PMID 15477419.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Gershov D, Kim S, Brot N, Elkon KB (November 2000). "C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response: Implications for Systemic Autoimmunity". J. Exp. Med. 192 (9): 1353–64. doi:10.1084/jem.192.9.1353. PMC 2193350. PMID 11067883.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Familian A, Zwart B, Huisman HG, Rensink I, Roem D, Hordijk PL, Aarden LA, Hack CE (July 2001). "Chromatin-independent binding of serum amyloid P component to apoptotic cells". J. Immunol. 167 (2): 647–54. doi:10.4049/jimmunol.167.2.647. PMID 11441067.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ a b Rovere P, Peri G, Fazzini F, Bottazzi B, Doni A, Bondanza A, Zimmermann VS, Garlanda C, Fascio U, Sabbadini MG, Rugarli C, Mantovani A, Manfredi AA (December 2000). "The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells". Blood. 96 (13): 4300–6. PMID 11110705.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Baruah P, Propato A, Dumitriu IE, Rovere-Querini P, Russo V, Fontana R, Accapezzato D, Peri G, Mantovani A, Barnaba V, Manfredi AA (January 2006). "The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens". Blood. 107 (1): 151–8. doi:10.1182/blood-2005-03-1112. PMID 16166594.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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