Inter-α-inhibitor impairs TSG-6-induced hyaluronan cross-linking.
Inter-α-inhibitor impairs TSG-6-induced hyaluronan cross-linking.
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DOI：
10.1074/jbc.m113.477422
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发表时间：
2013-10-11
期刊：
影响因子：
--
通讯作者：
Richter RP
中科院分区：
文献类型：
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作者：
Baranova NS;Foulcer SJ;Briggs DC;Tilakaratna V;Enghild JJ;Milner CM;Day AJ;Richter RP
背景：炎症/排卵相关蛋白TSG-6在富含透明质酸(HA)的细胞外基质中发挥多种功能。结果：I-α抑制物(I-α-I)影响HA-α-6相互作用，促进细胞黏附，促进I-TSG-I重链与HA形成共价复合体。结论：IαI决定TsG-6的活性，并改变HA基质的性质。意义：这些结果为调节HA-蛋白质相互作用和组装具有重要生物学意义的细胞外基质提供了新的见解。在炎症条件下，在卵丘-卵母细胞复合体的基质中，多糖透明质酸(HA)与血清糖蛋白α间抑制物(IαI)的重链(Hc)共价修饰。这改变了HA的功能特性以及它在细胞外基质中的结构作用。Hcs从IαI到HA的共价转移是由肿瘤坏死因子刺激基因-6(Tsg-6)催化的，但Tsg-6也是一种HA交联剂，可以诱导HA基质的缩合。在这里，我们通过研究IαI和TsG-6与端接的HA链上明确定义的膜的三元相互作用来研究Tsg-6这两个不同功能的相互作用。我们证明，在IαI存在的情况下，TsG-6介导的HA膜的交联性受到损害，并且这种作用抑制了Tsg-6介导的HA与CD44阳性细胞结合的增强。此外，我们发现在HA存在下，Tsg-6和IαI的相互作用产生了两种类型的络合物，它们独立地促进重链向HA的共价转移。其中一类络合物与HA的相互作用很弱，很可能与先前报道的共价HC·TSG-6络合物相对应。另一种类型的络合物是新颖的，可以稳定地结合到HA上，但不是共价的。与Tsg-6和IαI的长时间孵育会导致HA膜，除了共价结合的HA外，还包含几个紧密但非共价结合的分子物种。这些发现对于理解Tsg-6的生物学活性是如何调节的，从而IαI的存在与否将决定其功能具有重要的意义。
Background: Inflammation/ovulation-associated protein TSG-6 performs multiple functions in hyaluronan (HA)-rich extracellular matrices. Results: Inter-α-inhibitor (IαI) affects HA-TSG-6 interactions and enhancement of cell adhesion while promoting covalent complex formation between IαI heavy chains and HA. Conclusion: IαI dictates TSG-6 activity and remodels HA matrix properties. Significance: These results provide novel insights into the regulation of HA-protein interactions and assembly of biologically important extracellular matrices. 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 the HA matrix. 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 of HA gives rise to two types of complexes that independently promote the covalent transfer of heavy chains to HA. One type of complex interacts very weakly with HA and is likely to correspond to the previously reported covalent HC·TSG-6 complexes. The other type of complex is novel and binds stably but noncovalently to HA. Prolonged incubation with TSG-6 and IαI leads to HA films 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.