The molecular basis of inter-α-inhibitor heavy chain transfer on to hyaluronan

The inflammation-associated protein TSG-6 (the product of tumour necrosis factor-stimulated gene-6) can form covalent complexes with the heavy chains (HC1 and HC2) of IαI (inter-α-inhibitor); namely, TSG-6·HC1 and TSG-6·HC2, which act as intermediates in the covalent transfer of HCs on to the GAG (glycosaminoglycan) HA (hyaluronan). HC·HA, which is formed for example in the synovial fluids of arthritis patients, is more aggregated than unmodified HA and has altered mechanical and cell-binding properties. The expansion of the HA-rich cumulus ECM (extracellular matrix) during ovulation is critically dependent on the catalysis of HC·HA generation by TSG-6, with TSG-6^−/− mice being female infertile because of failure of HA cross-linking. It has been shown recently that TSG-6-mediated HC·HA formation is essential for the formation of HA-rich pericellular matrix and for cell migration in a model of wound healing. In contrast, in this model, the formation of cell-associated HA cable-like structures, although requiring the transfer of HCs on to HA, might not involve TSG-6. TSG-6-mediated HC transfer involves two sequential transesterification processes, where HCs are transferred from the CS (chondroitin sulfate) of IαI first on to TSG-6 and then on to HA. TSG-6 is an essential co-factor and catalyst in this chain of events, with both TSG-6·HC formation and HC transfer being dependent on the presence of Mg²⁺ or Mn²⁺ ions.