Inter-α-inhibitor impairs TSG-6-induced hyaluronan cross-linking

Natalia S. Baranova, Simon J. Foulcer, David C. Briggs, Viranga Tilakaratna, Jan J. Enghild, Caroline M. Milner, Anthony J. Day, Ralf P. Richter

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    Under inflammatory conditions and in the matrix of the cumulus-oocyte complex, the polysaccharide hyaluronan (HA) becomes decorated covalently with heavy chains (HCs) of the serum glycoprotein inter-α-inhibitor (IαI). This alters the functional properties of the HA as well as its structural role within extracellular matrices. The covalent transfer of HCs from IαI to HA is catalyzed by TSG-6 (tumor necrosis factor-stimulated gene-6), but TSG-6 is also known as a HA cross-linker that induces condensation of theHAmatrix. Here, we investigate the interplay of these two distinct functions of TSG-6 by studying the ternary interactions of IαI and TSG-6 with well defined films of end-grafted HA chains. We demonstrate that TSG-6-mediated cross-linking of HA films is impaired in the presence of IαI and that this effect suppresses the TSG-6-mediated enhancement of HA binding to CD44-positive cells. Furthermore, we find that the interaction of TSG-6 and IαI in the presence ofHA gives rise to two types of complexes that independently promote the covalent transfer of heavy chains to HA.Onetype of complex interacts very weakly with HA and is likely to correspond to the previously reported covalent HCαTSG-6 complexes. The other type of complex is novel and binds stably but noncovalently to HA. Prolonged incubation with TSG-6 and IαI leads toHAfilms that contain, in addition to covalently HA-bound HCs, several tightly but noncovalently bound molecular species. These findings have important implications for understanding how the biological activities of TSG-6 are regulated, such that the presence or absence of IαI will dictate its function. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
    Original languageEnglish
    Pages (from-to)29642-29653
    Number of pages11
    JournalJournal of Biological Chemistry
    Issue number41
    Publication statusPublished - 11 Oct 2013


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