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J. Biol. Chem., Vol. 282, Issue 41, 30161-30170, October 12, 2007

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PTX3 Interacts with Inter--trypsin Inhibitor

IMPLICATIONS FOR HYALURONAN ORGANIZATION AND CUMULUS OOPHORUS EXPANSION^*

Laura Scarchilli, Antonella Camaioni, Barbara Bottazzi, Veronica Negri, Andrea Doni, Livija Deban, Antonio Bastone^¶, Giovanni Salvatori^||1, Alberto Mantovani, Gregorio Siracusa, and Antonietta Salustri²

From the Department of Public Health and Cell Biology, University of Rome Tor Vergata, 00133 Rome, the Research Laboratory in Immunology and Inflammation, Istituto Clinico Humanitas, 20089 Rozzano, Milan, the ^¶Mario Negri Institute, 20157 Milan, Italy, and the ^||SigmaTau SpA, Pomezia, 00040 Rome, Italy

Pentraxin 3 (PTX3) and heavy chains (HCs) of inter--trypsin inhibitor (II) are essential for hyaluronan (HA) organization within the extracellular matrix of the cumulus oophorus, which is critical for in vivo oocyte fertilization and female fertility. In this study, we examined the possibility that these molecules interact and cooperate in this function. We show that HCs and PTX3 colocalize in the cumulus matrix and coimmunoprecipitate from cumulus matrix extracts. Coimmunoprecipitation experiments and solid-phase binding assays performed with purified human II and recombinant PTX3 demonstrate that their interaction is direct and not mediated by other matrix components. PTX3 does not bind to II subcomponent bikunin and, accordingly, bikunin does not compete for the binding of PTX3 to II, indicating that PTX3 interacts with II subcomponent HC only. Recombinant PTX3-specific N-terminal region, but not the PTX3-pentraxin C-terminal domain, showed the same ability as full-length protein to bind to HCs and to enable HA organization and matrix formation by Ptx3^-/- cumulus cell oocyte complexes cultured in vitro. Furthermore, a monoclonal antibody raised against PTX3 N terminus, which inhibits PTX3/II interaction, also prevents recombinant full-length PTX3 from restoring a normal phenotype to in vitro-cultured Ptx3^-/- cumuli. These results indicate that PTX3 directly interacts with HCs of II and that such interaction is essential for organizing HA in the viscoelastic matrix of cumulus oophorus, highlighting a direct functional link between the two molecules.

Received for publication, May 7, 2007 , and in revised form, July 26, 2007.

^* This work was supported by grants from Ministero Istruzione, Universitàe Ricerca (MIUR, Cofin) (to A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.

This article was selected as a Paper of the Week.

¹ An employee of the pharmaceutical company Sigma Tau, which holds patent rights on PTX3 and fertility.

² To whom correspondence should be addressed. Tel.: 39-06-7259-6168; Fax: 39-06-7259-6172; E-mail: salustri{at}med.uniroma2.it.

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