Incorporation of Pentraxin 3 into Hyaluronan Matrices is Tightly Regulated and Promotes Matrix Cross-Linking

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  • Natalia S Baranova, CIC biomaGUNE, Spain;, Spain
  • Antonio Inforzato, Humanitas Clinical and Research Center, Italy;, Italy
  • David C Briggs, University of Manchester, United Kingdom;, United Kingdom
  • Viranga Tilakaratna, University of Manchester, United Kingdom;, United Kingdom
  • Jan Johannes Enghild
  • Dhruv Thakar, Universite Grenoble Alpes, France., France
  • Caroline M Milner, University of Manchester, United Kingdom;, United Kingdom
  • Anthony J Day, University of Manchester, United Kingdom;, United Kingdom
  • Ralf P Richter, CIC biomaGUNE, Spain;, Spain

Mammalian oocytes are surrounded by a highly hydrated hyaluronan (HA)-rich extracellular matrix with embedded cumulus cells, forming the cumulus cell-oocyte complex (COC) matrix. The correct assembly, stability and mechanical properties of this matrix, which are crucial for successful ovulation, transport of the COC to the oviduct and its fertilization, depend on the interaction between HA and specific HA-organizing proteins. Although the proteins inter-αinhibitor (IαI), pentraxin 3 (PTX3) and TNF-stimulated gene-6 (TSG-6) have been identified as being critical for COC matrix formation, its supramolecular organization and the molecular mechanism of COC matrix stabilization remain unknown. Here we used films of end-grafted HA as a model system to investigate the molecular interactions involved in the formation and stabilization of HA matrices containing TSG-6, IαI and PTX3. We found that PTX3 binds neither to HA alone nor to HA films containing TSG-6. This long pentraxin also failed to bind to products of the interaction between IαI, TSG-6 and HA, among which are the covalent HC·HA and HC·TSG-6 complexes, despite the fact that both IαI and TSG-6 are ligands of PTX3. Interestingly, prior encounter with IαI was required for effective incorporation of PTX3 into TSG-6-loaded HA films. Moreover, we demonstrated that this ternary protein mixture made of IαI, PTX3 and TSG-6 is sufficient to promote formation of a stable (i.e. cross-linked) yet highly hydrated HA matrix. We propose that this mechanism is essential for correct assembly of the COC matrix, and may also have general implications in other inflammatory processes that are associated with HA-crosslinking.

Original languageEnglish
JournalJournal of Biological Chemistry
Pages (from-to)30481-30498
Number of pages13
Publication statusPublished - 4 Sep 2014

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