PTX3 explained

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] [5] 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.[6] [7] [8] [9] [10]

PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs.

Structure

Human and murine PTX3, localized in the syntenic 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. 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.[11]

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. PTX3 levels in cerebrospinal fluid help distinguishing between bacterial and aseptic meningoencephalitis.[12] Under these conditions, PTX3 is a rapid marker for primary local activation of innate immunity and inflammation.[13] [14] [15] [16] [17]

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.[18] [19] [20] 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.[20] [21]

Further reading

Notes and References

  1. Breviario F, d'Aniello EM, Golay J, Peri G, Bottazzi B, Bairoch A, Saccone S, Marzella R, Predazzi V, Rocchi M . Interleukin-1-inducible genes in endothelial cells. Cloning of a new gene related to C-reactive protein and serum amyloid P component . The Journal of Biological Chemistry . 267 . 31 . 22190–7 . November 1992 . 10.1016/S0021-9258(18)41653-5 . 1429570 . free .
  2. Web site: 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 . Structure of pentameric human serum amyloid P component . Nature . 367 . 6461 . 338–45 . January 1994 . 8114934 . 10.1038/367338a0 . 1994Natur.367..338E . 4284282 .
  4. Wirestam L, Enocsson H, Skogh T, Eloranta ML, Rönnblom L, Sjöwall C, Wetterö J . Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro . Clinical and Experimental Immunology . 189 . 1 . 83–91 . July 2017 . 28257596 . 5461103 . 10.1111/cei.12957 .
  5. Garlanda C, Bottazzi B, Bastone A, Mantovani A . Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility . Annual Review of Immunology . 23 . 337–66 . 2005 . 15771574 . 10.1146/annurev.immunol.23.021704.115756 .
  6. Diniz SN, Nomizo R, Cisalpino PS, Teixeira MM, Brown GD, Mantovani A, Gordon S, Reis LF, Dias AA . PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages . Journal of Leukocyte Biology . 75 . 4 . 649–56 . April 2004 . 14726497 . 10.1189/jlb.0803371 . 1172342 . free .
  7. 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 . 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 . The Journal of Biological Chemistry . 272 . 52 . 32817–23 . December 1997 . 9407058 . 10.1074/jbc.272.52.32817 . free .
  8. 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 . Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response . Nature . 420 . 6912 . 182–6 . November 2002 . 12432394 . 10.1038/nature01195 . 2002Natur.420..182G . 4414588 .
  9. 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 . Biochemical and functional characterization of the interaction between pentraxin 3 and C1q . European Journal of Immunology . 33 . 2 . 465–73 . February 2003 . 12645945 . 10.1002/immu.200310022 . 9479617 . free .
  10. 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-vivo fertilization . Development . 131 . 7 . 1577–86 . 10.1242/dev.01056 . 14998931 . free . free . 2434/758422.
  11. 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 . Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites . Blood . 87 . 5 . 1862–72 . March 1996 . 8634434 . 10.1182/blood.V87.5.1862.1862. free .
  12. Zatta M, Di Bella S, Bottazzi B, Rossi F, D'Agaro P, Segat L, Fabbiani M, Mantovani A, Luzzati R . 6 . Determination of pentraxin 3 levels in cerebrospinal fluid during central nervous system infections . European Journal of Clinical Microbiology & Infectious Diseases . December 2019 . 31813079 . 10.1007/s10096-019-03767-w . 39 . 4 . 665–670 . 208812200 . 11368/2972747 . free .
  13. Muller B, Peri G, Doni A, Torri V, Landmann R, Bottazzi B, Mantovani A . Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients . Critical Care Medicine . 29 . 7 . 1404–7 . July 2001 . 11445697 . 10.1097/00003246-200107000-00017 . 1709839 .
  14. 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 . PTX3 in small-vessel vasculitides: an independent indicator of disease activity produced at sites of inflammation . Arthritis and Rheumatism . 44 . 12 . 2841–50 . December 2001 . 11762945 . 10.1002/1529-0131(200112)44:12<2841::AID-ART472>3.0.CO;2-6 . free .
  15. 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 . Elevated plasma levels of the long pentraxin, pentraxin 3, in severe dengue virus infections . Journal of Medical Virology . 76 . 4 . 547–52 . August 2005 . 15977234 . 10.1002/jmv.20397 . 24762210 .
  16. Azzurri A, Sow OY, Amedei A, Bah B, Diallo S, Peri G, Benagiano M, D'Elios MM, Mantovani A, Del Prete G . IFN-gamma-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection . Microbes and Infection . 7 . 1 . 1–8 . January 2005 . 15716076 . 10.1016/j.micinf.2004.09.004 .
  17. 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 . Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction . Circulation . 110 . 16 . 2349–54 . October 2004 . 15477419 . 10.1161/01.CIR.0000145167.30987.2E . free .
  18. Gershov D, Kim S, Brot N, Elkon KB . 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 . The Journal of Experimental Medicine . 192 . 9 . 1353–64 . November 2000 . 11067883 . 2193350 . 10.1084/jem.192.9.1353 .
  19. Familian A, Zwart B, Huisman HG, Rensink I, Roem D, Hordijk PL, Aarden LA, Hack CE . Chromatin-independent binding of serum amyloid P component to apoptotic cells . Journal of Immunology . 167 . 2 . 647–54 . July 2001 . 11441067 . 10.4049/jimmunol.167.2.647 . free .
  20. 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 . The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells . Blood . 96 . 13 . 4300–6 . December 2000 . 11110705 . 10.1182/blood.V96.13.4300.
  21. Baruah P, Propato A, Dumitriu IE, Rovere-Querini P, Russo V, Fontana R, Accapezzato D, Peri G, Mantovani A, Barnaba V, Manfredi AA . 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 . January 2006 . 16166594 . 10.1182/blood-2005-03-1112 . free .

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