TSG6_MOUSE
ID TSG6_MOUSE Reviewed; 275 AA.
AC O08859;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 157.
DE RecName: Full=Tumor necrosis factor-inducible gene 6 protein;
DE AltName: Full=TNF-stimulated gene 6 protein;
DE Short=TSG-6;
DE AltName: Full=Tumor necrosis factor alpha-induced protein 6;
DE Short=TNF alpha-induced protein 6;
DE Flags: Precursor;
GN Name=Tnfaip6; Synonyms=Tnfip6, Tsg6;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE.
RC STRAIN=CD-1; TISSUE=Embryo, Oocyte, and Ovarian granulosa cell;
RX PubMed=9427551; DOI=10.1016/s0378-1119(97)00459-9;
RA Fueloep C., Kamath R.V., Li Y., Otto J.M., Salustri A., Olsen B.R.,
RA Glant T.T., Hascall V.C.;
RT "Coding sequence, exon-intron structure and chromosomal localization of
RT murine TNF-stimulated gene 6 that is specifically expressed by expanding
RT cumulus cell-oocyte complexes.";
RL Gene 202:95-102(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=12668637; DOI=10.1242/dev.00422;
RA Fueloep C., Szanto S., Mukhopadhyay D., Bardos T., Kamath R.V., Rugg M.S.,
RA Day A.J., Salustri A., Hascall V.C., Glant T.T., Mikecz K.;
RT "Impaired cumulus mucification and female sterility in tumor necrosis
RT factor-induced protein-6 deficient mice.";
RL Development 130:2253-2261(2003).
RN [4]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=18586671; DOI=10.1074/jbc.m802138200;
RA Mahoney D.J., Mikecz K., Ali T., Mabilleau G., Benayahu D., Plaas A.,
RA Milner C.M., Day A.J., Sabokbar A.;
RT "TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis
RT and osteoclast activation.";
RL J. Biol. Chem. 283:25952-25962(2008).
CC -!- FUNCTION: Major regulator of extracellular matrix organization during
CC tissue remodeling (By similarity). Catalyzes the transfer of a heavy
CC chain (HC) from inter-alpha-inhibitor (I-alpha-I) complex to
CC hyaluronan. Cleaves the ester bond between the C-terminus of the HC and
CC GalNAc residue of the chondroitin sulfate chain in I-alpha-I complex
CC followed by transesterification of the HC to hyaluronan. In the
CC process, potentiates the antiprotease function of I-alpha-I complex
CC through release of free bikunin (By similarity). Acts as a catalyst in
CC the formation of hyaluronan-HC oligomers and hyaluronan-rich matrix
CC surrounding the cumulus cell-oocyte complex, a necessary step for
CC oocyte fertilization (PubMed:12668637). Assembles hyaluronan in
CC pericellular matrices that serve as platforms for receptor clustering
CC and signaling. Enables binding of hyaluronan deposited on the surface
CC of macrophages to LYVE1 on lymphatic endothelium and facilitates
CC macrophage extravasation. Alters hyaluronan binding to functionally
CC latent CD44 on vascular endothelium, switching CD44 into an active
CC state that supports leukocyte rolling (By similarity). Modulates the
CC interaction of chemokines with extracellular matrix components and
CC proteoglycans on endothelial cell surface, likely preventing chemokine
CC gradient formation. In a negative feedback mechanism, may limit
CC excessive neutrophil recruitment at inflammatory sites by antagonizing
CC the association of CXCL8 with glycosaminoglycans on vascular
CC endothelium (By similarity). Has a role in osteogenesis and bone
CC remodeling. Inhibits BMP2-dependent differentiation of mesenchymal stem
CC cell to osteoblasts. Protects against bone erosion during inflammation
CC by inhibiting TNFSF11/RANKL-dependent osteoclast activation
CC (PubMed:18586671) (By similarity). {ECO:0000250|UniProtKB:P98066,
CC ECO:0000269|PubMed:12668637, ECO:0000269|PubMed:18586671}.
CC -!- SUBUNIT: Interacts (via Link domain) with inter-alpha-inhibitor (I-
CC alpha-I) component bikunin. Interacts with ITIH2/HC2; this interaction
CC is required for transesterification of the HC to hyaluronan. Interacts
CC (via Link and CUB domains) with ITIH1. Chondroitin sulfate may be
CC required for the stability of the complex. Interacts (via Link domain)
CC with various C-X-C and C-C chemokines including PF4, CXCL8, CXCL11,
CC CXCL12, CCL2, CCL7, CCL19, CCL21, and CCL27; this interaction
CC interferes with chemokine binding to glycosaminoglycans. Interacts
CC (primarily via Link domain) with BMP2; this interaction is inhibited by
CC hyaluronan. Interacts (via both Link and CUB domains) with TNFSF11.
CC Interacts (via CUB domain) with FN1 (via type III repeats 9-14); this
CC interaction enhances fibronectin fibril assembly. TNFAIP6 may act as a
CC bridging molecule between FN1 and THBS1.
CC {ECO:0000250|UniProtKB:P98066}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P98066}.
CC -!- TISSUE SPECIFICITY: Expressed in epiphyseal and metaphyseal bone marrow
CC of both the femur and tibia (at protein level).
CC {ECO:0000269|PubMed:18586671}.
CC -!- DEVELOPMENTAL STAGE: Expressed in cumulus cell-oocyte complexes during
CC expansion. {ECO:0000269|PubMed:9427551}.
CC -!- DOMAIN: The Link domain interacts with various extracellular matrix
CC components, including heparin, heparan sulfates, hyaluronan and I-
CC alpha-I complex. It is required for binding to various chemokines.
CC {ECO:0000250|UniProtKB:P98066}.
CC -!- DOMAIN: The CUB domain is necessary for calcium ion binding and
CC transesterification reaction. It is required for binding to FN1.
CC {ECO:0000250|UniProtKB:P98066}.
CC -!- DISRUPTION PHENOTYPE: Mutant female mice are infertile due to impaired
CC cumulus oophorus expansion upon gonadotropin surge (PubMed:12668637).
CC Mutant mice have twice the bone mass of wild-type littermates. They
CC show increased trabecular number and trabecular thickness
CC (PubMed:18586671). {ECO:0000269|PubMed:12668637,
CC ECO:0000269|PubMed:18586671}.
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DR EMBL; U83903; AAC53527.1; -; mRNA.
DR EMBL; BC021155; AAH21155.1; -; mRNA.
DR CCDS; CCDS16032.1; -.
DR PIR; JC6506; JC6506.
DR RefSeq; NP_033424.1; NM_009398.2.
DR AlphaFoldDB; O08859; -.
DR BMRB; O08859; -.
DR SMR; O08859; -.
DR STRING; 10090.ENSMUSP00000069231; -.
DR GlyGen; O08859; 2 sites.
DR iPTMnet; O08859; -.
DR PhosphoSitePlus; O08859; -.
DR PaxDb; O08859; -.
DR PRIDE; O08859; -.
DR ProteomicsDB; 298145; -.
DR Antibodypedia; 33651; 196 antibodies from 32 providers.
DR DNASU; 21930; -.
DR Ensembl; ENSMUST00000065927; ENSMUSP00000069231; ENSMUSG00000053475.
DR GeneID; 21930; -.
DR KEGG; mmu:21930; -.
DR UCSC; uc008jqp.1; mouse.
DR CTD; 7130; -.
DR MGI; MGI:1195266; Tnfaip6.
DR VEuPathDB; HostDB:ENSMUSG00000053475; -.
DR eggNOG; KOG1218; Eukaryota.
DR eggNOG; KOG3714; Eukaryota.
DR GeneTree; ENSGT00940000157201; -.
DR HOGENOM; CLU_092089_0_0_1; -.
DR InParanoid; O08859; -.
DR OMA; DDTACMA; -.
DR OrthoDB; 934805at2759; -.
DR PhylomeDB; O08859; -.
DR TreeFam; TF334173; -.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR BioGRID-ORCS; 21930; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Tnfaip6; mouse.
DR PRO; PR:O08859; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; O08859; protein.
DR Bgee; ENSMUSG00000053475; Expressed in 1st arch maxillary component and 168 other tissues.
DR ExpressionAtlas; O08859; baseline and differential.
DR Genevisible; O08859; MM.
DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0052689; F:carboxylic ester hydrolase activity; ISS:UniProtKB.
DR GO; GO:0001968; F:fibronectin binding; ISS:UniProtKB.
DR GO; GO:0005540; F:hyaluronic acid binding; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:1905590; P:fibronectin fibril organization; ISS:UniProtKB.
DR GO; GO:0030212; P:hyaluronan metabolic process; ISS:UniProtKB.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISO:MGI.
DR GO; GO:0090024; P:negative regulation of neutrophil chemotaxis; ISS:UniProtKB.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; ISS:UniProtKB.
DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; ISS:UniProtKB.
DR GO; GO:0001550; P:ovarian cumulus expansion; IMP:UniProtKB.
DR GO; GO:0030728; P:ovulation; IEA:Ensembl.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:1903911; P:positive regulation of receptor clustering; ISS:UniProtKB.
DR CDD; cd00041; CUB; 1.
DR Gene3D; 2.60.120.290; -; 1.
DR Gene3D; 3.10.100.10; -; 1.
DR InterPro; IPR016186; C-type_lectin-like/link_sf.
DR InterPro; IPR016187; CTDL_fold.
DR InterPro; IPR000859; CUB_dom.
DR InterPro; IPR000538; Link_dom.
DR InterPro; IPR035914; Sperma_CUB_dom_sf.
DR Pfam; PF00431; CUB; 1.
DR Pfam; PF00193; Xlink; 1.
DR PRINTS; PR01265; LINKMODULE.
DR SMART; SM00042; CUB; 1.
DR SMART; SM00445; LINK; 1.
DR SUPFAM; SSF49854; SSF49854; 1.
DR SUPFAM; SSF56436; SSF56436; 1.
DR PROSITE; PS01180; CUB; 1.
DR PROSITE; PS01241; LINK_1; 1.
DR PROSITE; PS50963; LINK_2; 1.
PE 1: Evidence at protein level;
KW Calcium; Cell adhesion; Disulfide bond; Glycoprotein; Hydrolase;
KW Metal-binding; Reference proteome; Secreted; Signal.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..275
FT /note="Tumor necrosis factor-inducible gene 6 protein"
FT /evidence="ECO:0000255"
FT /id="PRO_0000026693"
FT DOMAIN 36..129
FT /note="Link"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00323"
FT DOMAIN 135..247
FT /note="CUB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT REGION 253..275
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 253..267
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 183
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P98066"
FT BINDING 191
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P98066"
FT BINDING 232
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P98066"
FT BINDING 234
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P98066"
FT BINDING 235
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P98066"
FT CARBOHYD 118
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 258
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 58..127
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00323"
FT DISULFID 82..103
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00323"
FT DISULFID 135..161
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT DISULFID 188..210
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
SQ SEQUENCE 275 AA; 30924 MW; 1CD247228260B8F9 CRC64;
MVVLLCLCVL LWEEAHGWGF KNGIFHNSIW LEQAAGVYHR EARAGRYKLT YAEAKAVCEF
EGGRLATYKQ LEAARKIGFH VCAAGWMAKG RVGYPIVKPG PNCGFGKTGI IDYGIRLNRS
ERWDAYCYNP HAKECGGVFT DPKRIFKSPG FPNEYDDNQV CYWHIRLKYG QRIHLSFLDF
DLEHDPGCLA DYVEIYDSYD DVHGFVGRYC GDELPEDIIS TGNVMTLKFL SDASVTAGGF
QIKYVTVDPA SKSSQAKNTS TTGNKKFLPG RFSHL
