TNFAIP6

TNFAIP6 is a secretory protein that contains a hyaluronan-binding domain, and thus is a member of the hyaluronan-binding protein family. The hyaluronan-binding domain is known to be involved in extracellular matrix stability and cell migration. It has been shown to form a stable complex with inter-alpha-inhibitor (I alpha I), and thus enhance the serine protease inhibitory activity of I alpha I, which is important in the protease network associated with inflammation. TNFAIP6 can be induced by proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-1. Enhanced levels of this protein are found in the synovial fluid of patients with osteoarthritis and rheumatoid arthritis.

Full Name

TNF Alpha Induced Protein 6

Function

Major regulator of extracellular matrix organization during tissue remodeling (PubMed:18042364, PubMed:26823460, PubMed:15917224).
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:20463016, PubMed:15917224, PubMed:16873769).
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:26823460, PubMed:15060082).
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:18586671, PubMed:16771708).
Protects against bone erosion during inflammation by inhibiting TNFSF11/RANKL-dependent osteoclast activation (PubMed:18586671).

Biological Process

Biological Process cell adhesionSource:UniProtKB-KW
Biological Process cell-cell signalingSource:ProtInc1 Publication
Biological Process fibronectin fibril organizationSource:UniProtKB1 Publication
Biological Process hyaluronan metabolic processSource:UniProtKB2 Publications
Biological Process inflammatory responseSource:ProtInc1 Publication
Biological Process negative regulation of BMP signaling pathwaySource:UniProtKB1 Publication
Biological Process negative regulation of inflammatory responseSource:CACAO1 Publication
Biological Process negative regulation of neutrophil chemotaxisSource:UniProtKB1 Publication
Biological Process negative regulation of osteoblast differentiationSource:UniProtKB2 Publications
Biological Process negative regulation of osteoclast differentiationSource:UniProtKB1 Publication
Biological Process ovarian cumulus expansionSource:UniProtKB
Biological Process ovulationSource:Ensembl
Biological Process positive regulation of cell migrationSource:Ensembl
Biological Process positive regulation of receptor clusteringSource:UniProtKB1 Publication
Biological Process signal transductionSource:ProtInc1 Publication

Cellular Location

Secreted

PTM

N-glycosylated.