Alternative titles; symbols
HGNC Approved Gene Symbol: TNFAIP6
Cytogenetic location: 2q23.3 Genomic coordinates (GRCh38): 2:151,357,592-151,381,340 (from NCBI)
TSG6 is a member of the hyaluronan (HA)-binding protein family, which includes cartilage link protein (HAPLN1; 115435), proteoglycan core protein (e.g., 118661), and the adhesion receptor CD44 (107269) (Lee et al., 1992).
Lee et al. (1992) isolated TSG6 from a library made from tumor necrosis factor-alpha (TNF; 191160)-treated human fibroblasts. The predicted polypeptide is 277 amino acids long and includes a typical cleavage signal peptide. TSG6 is highly homologous to CD44, particularly in the hyaluronic acid-binding domain. Western blots with antibodies made to a TSG6 fusion protein detected a 39-kD glycoprotein in TNF-treated cells.
Lee et al. (1993) showed by Southern blot analysis that TSG6 is a single-copy gene in humans and mice. They assigned the TSG6 gene to chromosome 2 by use of a panel of somatic cell hybrids.
By radiation hybrid analysis, Nentwich et al. (2002) mapped the TSG6 gene to chromosome 2q23.3.
By coprecipitation analysis, Lee et al. (1992) showed that human TSG6 bound hyaluronate.
Lee et al. (1993) demonstrated that TSG6 is transcribed in normal fibroblasts and activated by binding of the cytokines TNF and interleukin-1 (IL1; 147720; 147760) at AP1 (JUN; 165160) and NF-IL6 (CEBPB; 189965) sites in its promoter.
Klampfer et al. (1994) showed that the CEBPB site is essential for activation of the TSG6 promoter by TNF or IL1. The JUN site cooperates with the CEBPB site in the activation of the TSG6 promoter by both TNFA and IL1.
Klampfer et al. (1994) suggested that the presence of TSG6 in synovial fluid suggests a possible role in rheumatoid arthritis.
Lesley et al. (2004) noted that the HA-binding domains of TSG6 and CD44 both contain a structural unit of about 100 amino acids called a Link module. They showed that preincubation of HA with full-length recombinant human TSG6 or its Link module enhanced or induced binding of HA to cell surface CD44 on constitutive and inducible cell backgrounds, respectively. TSG6 Link module mutants with impaired HA binding had reduced ability to modulate ligand binding by cell surface CD44.
By analyzing chicken and mouse embryos, Sivakumar et al. (2018) found that morphologic asymmetry in the dorsal mesentery (DM) is first broken on the right side of the DM of embryos, not on the left, where Pitx2 (601542) is expressed and has been the focal point in governing organ laterality. The symmetry-breaking event in embryos depends on the accumulation of hyaluronan (HA), and is independent of Pitx2 in determining the gut and vascular laterality. While HA is synthesized bilaterally in the DM of embryos, Tsg6 covalently modifies HA on the right side of embryo to result in asymmetric accumulation of HA on the right, which then triggers dramatic expansion of the right side of the DM necessary for midgut rotation and gut vascular development, linking vessel patterning with the morphogenesis of the host organ. Analysis of the molecular distribution of HA, Tsg6, and the critical substrate (inter-alpha-trypsin inhibitor; see AMBP, 176870) for Tsg6 to form modified HA revealed that the molecular machinery involved in modification of HA on the right is conserved between chicken, mouse, and rat. Tsg6 -/- mice showed potentially lethal or sublethal phenotypes associated with Tsg6 loss, but some Tsg6 -/- mice were viable; females were infertile. Loss of Tsg6 in knockout mice caused failure to initiate midgut rotation. Unmodified HA on the left side plays a distinct role compared with the right and is necessary to maintain proper Pitx2 expression and function within the left DM. Knockdown of Pitx2 on the left side of the chicken embryo had no effect on the levels of HA on the left side, indicating that Tsg6-HA pathway for the left-right symmetry-breaking is independent of Pitx2 on the left.
Nentwich et al. (2002) identified a nonsynonymous SNP, 431G-A, resulting in an arg144-to-gln change in the CUB domain of TSG6. Genotyping of 400 individuals with osteoarthritis (see 165720), which has been linked to chromosome 2q, and 400 controls showed that gln144 is the major form of TSG6 in Caucasians, with over 75% being gln144 homozygotes. Although modeling indicated that the amino acid change might lead to functional differences, no association was found between the polymorphism and susceptibility to osteoarthritis.
Nagyeri et al. (2011) found a significant correlation between serum Tsg6 concentration and arthritis severity in a cartilage proteoglycan (aggrecan)-induced mouse model of rheumatoid arthritis (180300). Immunoblot and fluorescence microscopy detected Tsg6 in arthritic joint tissue together with the heavy chains of inter-alpha-trypsin inhibitor (I-alpha-I) (see 147270). Highest levels of Tsg6 were found in the secretory granules of mast cells, where it colocalized with mast cell protease-6 (MCP6, or TPSB2; 191081). In vitro, Tsg6 formed complexes with Mcp6 and Mcp7 (TPSAB1; 191080) via either heparin or HA. Tsg6 suppressed inflammatory tissue destruction by enhancing serine protease-inhibitory activity of I-alpha-I against plasmin (173350) by transferring I-alpha-I heavy chains to HA, thus liberating the I-alpha-I light chain, bikunin (176870). Nagyeri et al. (2011) proposed that TSG6 promotes inhibition of tryptase activity via a mechanism similar to inhibition of plasmin.
Klampfer, L., Lee, T. H., Hsu, W., Vilcek, J., Chen-Kiang, S. NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1. Molec. Cell. Biol. 14: 6561-6569, 1994. [PubMed: 7935377] [Full Text: https://doi.org/10.1128/mcb.14.10.6561-6569.1994]
Lee, T. H., Klampfer, L., Shows, T. B., Vilcek, J. Transcriptional regulation of TSG6, a tumor necrosis factor- and interleukin-1-inducible primary response gene coding for a secreted hyaluronan-binding protein. J. Biol. Chem. 268: 6154-6160, 1993. [PubMed: 8454591]
Lee, T. H., Wisniewski, H.-G., Vilcek, J. A novel secretory tumor necrosis-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44. J. Cell. Biol. 116: 545-557, 1992. [PubMed: 1730767] [Full Text: https://doi.org/10.1083/jcb.116.2.545]
Lesley, J., Gal, I., Mahoney, D. J., Cordell, M. R., Rugg, M. S., Hyman, R., Day, A. J., Mikecz, K. TSG-6 modulates the interaction between hyaluronan and cell surface CD44. J. Biol. Chem. 279: 25745-25754, 2004. [PubMed: 15060082] [Full Text: https://doi.org/10.1074/jbc.M313319200]
Nagyeri, G., Radacs, M., Ghassemi-Nejad, S., Tryniszewska, B., Olasz, K., Hutas, G., Gyorfy, Z., Hascall, V. C., Glant, T. T., Mikecz, K. TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin. J. Biol. Chem. 286: 23559-23569, 2011. [PubMed: 21566135] [Full Text: https://doi.org/10.1074/jbc.M111.222026]
Nentwich, H. A., Mustafa, Z., Rugg, M. S., Marsden, B. D., Cordell, M. R., Mahoney, D. J., Jenkins, S. C., Dowling, B., Fries, E., Milner, C. M., Loughlin, J., Day, A. J. 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. 277: 15354-15362, 2002. [PubMed: 11854277] [Full Text: https://doi.org/10.1074/jbc.M110765200]
Sivakumar, A., Mahadevan, A., Lauer, M. E., Narvaez, R. J., Ramesh, S., Demler, C. M., Souchet, N. R., Hascall, V. C., Midura, R. J., Garantziotis, S., Frank, D. B., Kimata, K., Kurpios, N. A. Midgut laterality is driven by hyaluronan on the right. Dev. Cell 46: 533-551, 2018. [PubMed: 30174180] [Full Text: https://doi.org/10.1016/j.devcel.2018.08.002]