TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy)

2007-12-01   Jiangping Wu , Bing Han 

CHUM Research Center, University of Montreal, Canada




Atlas Image


DNA sequence is located on chromosome 20. Transcription consists of 7 exons and 6 introns, spanning 3.6kb.
A shorter transcription variance (M68E) has been identified, and is transcribed from 3 exons and 2 introns spanning 1.9kb as illustrated above. The difference occurs at the 5 untranslated region, but the two transcripts encode the same isoform. Mice do not have a gene orthologue to human TNFRSF6B.
TNFRSF68B mRNA in Northen blot presents as a 1.2-knt band.


Atlas Image
A) Domains and Motifs. B) TNFRSF6B X-ray crystography


TNFRSF6B protein is 300-amino acid long, and has a molecular weight of 35 kD. Although TNFRSF6B belongs to the TNFR superfamily, it lacks the transmembrane and cytosolic domains in its sequence, and is a secreted protein. It contains 4 TNFR cystein-rich regions, as illustrated above.
TNFRSF6B can be easily cleaved between Arg218 and Ala219 in biological fluids and solutions. It has thus a very short (about 20 min) half-life in serum and in vivo. Mutation of arginine residue at position 218 to glutamine makes TNFRSF6B resistant to proteolysis, and significantly prolongs its half-life.
TNFRSF6B can bind to the TNF family members FasL, LIGHT and TL1A. It does not bind to other known TNF family members. Human TNFRSF6B can bind to mouse FasL, LIGHT and TL1A. This allows human DcR3/TNFRSF6B to function in mouse models both in vitro and in vivo.
The role of TNFRSF6B in apoptosis is obvious. FasL is a well-known molecule involved in apoptosis. LIGHT is a ligand for HVEM and LTbetaR, in addition to being a ligand for TNFRSF6B. LIGHT can induce apoptosis in cells expressing both HVEM and LTbetaR, or LTbetaR alone. TL1A, a member of the TNF family, can evoke apoptosis via its receptor, DR3. Consequently, the interaction of TNFRSF6B with FasL, LIGHT, and TL1A blocks apoptosis mediated by Fas, HVEM, LTbetaR and DR3.


Normal tissue and cells express low-level TNFRSF6B, and healthy individuals have near-background serum TNFRSF6B levels. About 60% of malignant tumors of various tissue origins overexpress TNFRSF6B, and these patients have elevated serum TNFRSF6B levels. Serum TNFRSF6B levels of tumor patients are positively correlated to the degree of tumor malignancy and status of metastasis. It is hypothesized that malignant tumor cells secrete TNFRSF6B as a way to achieve survival advantage by blocking multiple apoptosis pathways.
Hepatocytes in liver cirrhosis have augmented TNFRSF6B expression and patients with liver cirrhosis have increased serum TNFRSF6B levels.
TNFRSF6B expression is low in resting T cells but is augmented in activated T cells, which probably represents a fine-tuning mechanism to balance the need for clonal expansion and subsequent massive activation-induced T cell death. About 40% of systemic lupus erythematosus patients have elevated serum TNFRSF6B levels.
TNFRSF6B expression in rheumatoid arthritis fibroblast-like synoviocytes is increased by TNFalpha


TNFRSF6B is a secreted protein, and is thus detected in body fluids. However, it can also be detected in cytoplasm before it is secreted.


As TNFRSF6B can block ligands from interacting with Fas, HVEM, LTbetaR, and DR3, all of which mediate apoptosis, it is thus can effectively inhibit apoptosis in many cell types. It is believed that many types of malignant tumors gain survival advantage by secreting TNFRSF6B which blocks tumor cell apoptosis.
Syngeneic islets transplanted to diabetes recipients survive better in the presence of administered exogenous human TNFRSF6B, due to the blockage of FasL-, LIGHT- and TL1A-triggered islets apoptosis. Transgenic expression of human TNFRSF6B in NOD mouse islets reduces diabetes pathogenesis, again, due to anti-apoptotic effect of TNFRSF6B.
The forward signaling from FasL to Fas, and from LIGHT to HVEM can provide costimulation signals to resting T cells. Blocking of these two signaling pathways reduces T cell responses to antigens. As LIGHT and FasL, although being ligands, are also transmembrane proteins, and are capable of reversely transducing costimulating signals into T cells, TNFRSF6B can also block such reverse signaling. The end result is that TNFRSF6B can reduce several costimulation pathways in T cells and inhibit T cell immune responses, such as cytokine secretion and proliferation in vitro, and cardiac allograft rejection in vivo in mouse models.
When human TNFRSF6B is linked to a transmembrane domain and is expressed on the mouse tumor cell surface, it can effectively trigger T cell costimulation via LIGHT and FasL reverse signaling, and cause effective tumor vaccination in mouse models.
When human TNFRSF6B is transgenically expressed in mice, it causes a systemic lupus erythrematosus-like syndrome. The expression of TNFRSF6B in bone marrow-derived cells is sufficient to induce this phenotype.
Recombinant human TNFRSF6B ameliorates an autoimmune crescentic glomerulonephritis model in mice.
TNFRSF6B can influence dendritic cells which in turn drive T cells to differentiate into Th2 cells.
TNFRSF6B can inhibit actin polymerization of T cells upon mitogen stimulation, and repress T-cell pseudopodium formation, which is known to be important for cell-cell interaction. As a consequence, T-cell aggregation after activation is suppressed by either soluble or solid phase TNFRSF6B.
Human T cells pretreated with soluble or solid-phase TNFRSF6B are compromised in migration in vitro and in vivo toward CXCL12. Mechanistically, a small GTPase Cdc42 fails to be activated after TNFRSF6B pretreatment of human T cells, and further downstream, p38 mitogen-activated protein kinase activation, actin polymerization, and pseudopodium formation are all down-regulated in the treated T cells.
Phagocytic activity toward immune complexes and apoptotic bodies as well as the production of free radicals and proinflammatory cytokines in response to lipopolysaccharide are impaired in TNFRSF6B-treated macrophages.



Not reported yet.

Implicated in

Entity name
Malignant tumors
TNFRSF6B is overexpressed in about 60% of various malignant tumors. Its anti-apoptotic effect provides the tumors a survival advantage, and its role in reducing T cell costimulation favors tumor evasion from the immune surveillance. No TNFRSF6B gene amplification in tumors has been identified.
Diagnosis and prognosis
TNFRSF6B in sera or tumor can be used as a parameter for tumor diagnosis and prognosis. The degree of tumor malignancy is correlated to TNFRSF6B levels. When a TNFRSF6B-expressing tumor is resected, serum TNFRSF6B levels will decrease to near-zero level. The re-arising of serum TNFRSF6B in such patients will indicate tumor reoccurrence.
When TNFRSF6B is anchored on tumor cell surface, it can increase the antigenicity of the tumor, and such TNFRSF6B-expressing tumors can be used as tumor vaccine.
Entity name
Systemic lupus erythematosus (SLE)
About 50% of SLE patients have elevated serum TNFRSF6B levels, and the levels augment during SLE flare-up. In animal models, human TNFRSF6B overexpression in mouse cells of hematopoietic origin leads to a SLE-like syndrome, suggesting a pathogenic role of TNFRSF6B in SLE.
Serum TNFRSF6B can be used as a diagnostic parameter for SLE and SLE disease activity.
Due to the pathogenic effect of TNFRSF6B on SLE, it is speculated that neutralizing TNFRSF6B might have therapeutic effect on a subpopulation of SLE patients, who are serum TNFSF6B positive.
Entity name
Islet primary nonfunction during islet transplantation
Due to the anti-apoptotic effect of TNFRSF6B, it can effectively protect islets from apoptosis during their isolation, transportation, and primary non-function after transplantation.


Pubmed IDLast YearTitleAuthors
156272062005Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma.Arakawa Y et al
106555132000Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster.Bai C et al
128782042003Characterization of chicken TNFR superfamily decoy receptors, DcR3 and osteoprotegerin.Bridgham JT et al
163654082006The glycosaminoglycan-binding domain of decoy receptor 3 is essential for induction of monocyte adhesion.Chang YC et al
146572142004Modulation of macrophage differentiation and activation by decoy receptor 3.Chang YC et al
148715352004Quantification and detection of DcR3, a decoy receptor in TNFR family.Chen J et al
168562052006Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells.Fayad R et al
152151852004Soluble receptor (DcR3) and cellular inhibitor of apoptosis-2 (cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis.Gill RM et al
179689502007Overexpression of human decoy receptor 3 in mice results in a systemic lupus erythematosus-like syndrome.Han B et al
173934152007Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against Fas-induced apoptosis.Hayashi S et al
173011272007Epstein-Barr virus transcription activator Rta upregulates decoy receptor 3 expression by binding to its promoter.Ho CH et al
146973322004Enhanced adhesion of monocytes via reverse signaling triggered by decoy receptor 3.Hsu MJ et al
119944332002Modulation of dendritic cell differentiation and maturation by decoy receptor 3.Hsu TL et al
162106172005Attenuation of Th1 response in decoy receptor 3 transgenic mice.Hsu TL et al
151248962004Serum concentration of soluble decoy receptor 3 in glioma patients before and after surgery.Hwang SL et al
176870762007Decoy receptor 3 ameliorates an autoimmune crescentic glomerulonephritis model in mice.Ka SM et al
158936962005Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia.Kim S et al
146880852004Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial antigens in human monocytes and myeloid dendritic cells.Kim S et al
160403012005Overexpression of decoy receptor 3 in precancerous lesions and adenocarcinoma of the esophagus.Li H et al
119078382001Ultraviolet light (UV) regulation of the TNF family decoy receptors DcR2 and DcR3 in human keratinocytes.Maeda T et al
123976452002DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer.Mild G et al
110980892000Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas.Ohshima K et al
166363002006Alterations of Fas and Fas-related molecules in patients with silicosis.Otsuki T et al
106326702000Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients.Otsuki T et al
98723211998Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer.Pitti RM et al
112891592001Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis.Roth W et al
162736012005Overexpression of decoy receptor 3 in hepatocellular carcinoma and its association with resistance to Fas ligand-mediated apoptosis.Shen HW et al
158146972005Tumor vaccine based on cell surface expression of DcR3/TR6.Shi G et al
145006352003Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo.Shi G et al
174907322007Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer.Simon I et al
150788962004Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical-induced autoimmune destruction in nonobese diabetic mice.Sung HH et al
121115802002The prognostic significance of overexpression of the decoy receptor for Fas ligand (DcR3) in patients with gastric carcinomas.Takahama Y et al
170992182007Attenuation of bone mass and increase of osteoclast formation in decoy receptor 3 transgenic mice.Tang CH et al
127947522003Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma.Tsuji S et al
127618932003DcR3/TR6 modulates immune cell interactions.Wan X et al
124711132002A TNF family member LIGHT transduces costimulatory signals into human T cells.Wan X et al
145112362003Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue.Wortinger MA et al
125660952003Decoy receptor 3 (DcR3) is proteolytically processed to a metabolic fragment having differential activities against Fas ligand and LIGHT.Wroblewski VJ et al
146340662004Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication.Wu SF et al
127409252003Clinical significance of detecting elevated serum DcR3/TR6/M68 in malignant tumor patients.Wu Y et al
154753692004Sensitization of cells to TRAIL-induced apoptosis by decoy receptor 3.Wu YY et al
156619282005Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression.Yang CR et al
150020402004Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells.Yang CR et al
180066942008Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3).You RI et al
103187731999A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis.Yu KY et al
113904282001Modulation of T-cell responses to alloantigens by TR6/DcR3.Zhang J et al

Other Information

Locus ID:

NCBI: 8771
MIM: 603361
HGNC: 11921
Ensembl: ENSG00000243509


dbSNP: 8771
ClinVar: 8771
TCGA: ENSG00000243509


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
TNFR2 non-canonical NF-kB pathwayREACTOMER-HSA-5668541
TNFs bind their physiological receptorsREACTOMER-HSA-5669034

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
187584642008Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.113
187584642008Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.113
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
192047262009Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.63
183493192008Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3.38
186766802008Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway.32
187572432008Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis.32
119944332002Modulation of dendritic cell differentiation and maturation by decoy receptor 3.27
180066942008Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3).27
213002862011Decoy strategies: the structure of TL1A:DcR3 complex.26


Jiangping Wu ; Bing Han

TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy)

Atlas Genet Cytogenet Oncol Haematol. 2007-12-01

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