TNFAIP6

Description

The TNFAIP6 (TNF alpha induced protein 6) is a protein-coding gene located on chromosome 2.

Tumor necrosis factor-inducible gene 6 protein also known as Hyaluronate-binding protein, TNF-stimulated gene 6 protein, Tumor necrosis factor alpha-induced protein 6. 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). 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).

TNFAIP6 is a major regulator of extracellular matrix organization during tissue remodeling. It catalyzes the transfer of a heavy chain (HC) from the inter-alpha-inhibitor (I-alpha-I) complex to hyaluronan, cleaving the ester bond between the C-terminus of the HC and GalNAc residue of the chondroitin sulfate chain in the I-alpha-I complex, followed by transesterification of the HC to hyaluronan. This process potentiates the antiprotease function of the I-alpha-I complex through the release of free bikunin. TNFAIP6 acts as a catalyst in the formation of hyaluronan-HC oligomers and a hyaluronan-rich matrix surrounding the cumulus cell-oocyte complex, which is necessary for oocyte fertilization. It assembles hyaluronan in pericellular matrices that serve as platforms for receptor clustering and signaling. TNFAIP6 enables the binding of hyaluronan deposited on the surface of macrophages to LYVE1 on lymphatic endothelium and facilitates macrophage extravasation. It alters hyaluronan binding to functionally latent CD44 on vascular endothelium, switching CD44 into an active state that supports leukocyte rolling. TNFAIP6 modulates the interaction of chemokines with extracellular matrix components and proteoglycans on the endothelial cell surface, likely preventing chemokine gradient formation. In a negative feedback mechanism, TNFAIP6 may limit excessive neutrophil recruitment at inflammatory sites by antagonizing the association of CXCL8 with glycosaminoglycans on vascular endothelium. TNFAIP6 plays a role in osteogenesis and bone remodeling. It inhibits BMP2-dependent differentiation of mesenchymal stem cells to osteoblasts and protects against bone erosion during inflammation by inhibiting TNFSF11/RANKL-dependent osteoclast activation.

TNFAIP6 is also known as TSG-6, TSG6.

Associated Diseases

WES Whole Exome Sequencing