Recombinant Human Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)

Function

Major regulator of extracellular matrix organization during tissue remodeling (PubMed:15917224, PubMed:18042364, PubMed:26823460). Catalyzes the transfer of a heavy chain (HC) from inter-alpha-inhibitor (I-alpha-I) complex to hyaluronan. Cleaves the ester bond between the C-terminus of the HC and GalNAc residue of the chondroitin sulfate chain in I-alpha-I complex followed by transesterification of the HC to hyaluronan. In the process, potentiates the antiprotease function of I-alpha-I complex through release of free bikunin (PubMed:15917224, PubMed:16873769, PubMed:20463016). Acts as a catalyst in the formation of hyaluronan-HC oligomers and hyaluronan-rich matrix surrounding the cumulus cell-oocyte complex, a necessary step for oocyte fertilization (PubMed:26468290). Assembles hyaluronan in pericellular matrices that serve as platforms for receptor clustering and signaling. Enables binding of hyaluronan deposited on the surface of macrophages to LYVE1 on lymphatic endothelium and facilitates macrophage extravasation. Alters hyaluronan binding to functionally latent CD44 on vascular endothelium, switching CD44 into an active state that supports leukocyte rolling (PubMed:15060082, PubMed:26823460). Modulates the interaction of chemokines with extracellular matrix components and proteoglycans on endothelial cell surface, likely preventing chemokine gradient formation (PubMed:27044744). In a negative feedback mechanism, may limit excessive neutrophil recruitment at inflammatory sites by antagonizing the association of CXCL8 with glycosaminoglycans on vascular endothelium (PubMed:24501198). Has a role in osteogenesis and bone remodeling. Inhibits BMP2-dependent differentiation of mesenchymal stem cell to osteoblasts (PubMed:16771708, PubMed:18586671). Protects against bone erosion during inflammation by inhibiting TNFSF11/RANKL-dependent osteoclast activation (PubMed:18586671)

Subcellular Location

Secreted

Tissue Specificity

Expressed in airway epithelium and submucosal gland (at protein level). Colocalizes with bikunin at the ciliary border. Present in bronchoalveolar lavage fluid (at protein level) (PubMed:16873769). Expressed in mesenchymal stem cells (PubMed:16771708). Found in the synovial fluid of patients with rheumatoid arthritis

Subunit

Interacts (via Link domain) with inter-alpha-inhibitor (I-alpha-I) component bikunin (PubMed:15917224). Interacts with ITIH2/HC2; this interaction is required for transesterification of the HC to hyaluronan (PubMed:20463016). Interacts (via Link and CUB domains) with ITIH1 (PubMed:26468290). Chondroitin sulfate may be required for the stability of the complex (PubMed:7516184). Interacts (via Link domain) with various C-X-C and C-C chemokines including PF4, CXCL8, CXCL11, CXCL12, CCL2, CCL7, CCL19, CCL21, and CCL27; this interaction interferes with chemokine binding to glycosaminoglycans (PubMed:24501198, PubMed:27044744). Interacts (primarily via Link domain) with BMP2; this interaction is inhibited by hyaluronan (PubMed:16771708). Interacts (via both Link and CUB domains) with TNFSF11 (PubMed:18586671). Interacts (via CUB domain) with FN1 (via type III repeats 9-14); this interaction enhances fibronectin fibril assembly. TNFAIP6 may act as a bridging molecule between FN1 and THBS1 (PubMed:18042364)

• Lee T.H. et al. A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44. — J. Cell Biol. (1992)
• Nentwich H.A. et al. A novel allelic variant of the human TSG-6 gene encoding an amino acid difference in the CUB module. Chromosomal localization, frequency analysis, modeling, and expression. — J. Biol. Chem. (2002)
• Hillier L.W. et al. Generation and annotation of the DNA sequences of human chromosomes 2 and 4. — Nature (2005)
• Mural R.J. et al. PubMed: CI-5GBD0VIIJ7C63 (SEP-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Wisniewski H.-G. et al. TSG-6, an arthritis-associated hyaluronan binding protein, forms a stable complex with the serum protein inter-alpha-inhibitor. — Biochemistry (1994)
• Lesley J. et al. TSG-6 modulates the interaction between hyaluronan and cell surface CD44. — J. Biol. Chem. (2004)
• Mahoney D.J. et al. Characterization of the interaction between tumor necrosis factor-stimulated gene-6 and heparin: implications for the inhibition of plasmin in extracellular matrix microenvironments. — J. Biol. Chem. (2005)