Tumor necrosis factor receptor superfamily (TNFRSF); Members of TNFR superfamily (TNFRSF) interactions with TNF superfamily (TNFSF) ligands (TNFL) control key cellular processes such as differentiation, proliferation, apoptosis, and cell growth. Dysregulation of these pathways has been shown to result in a wide range of pathological conditions, including autoimmune diseases, inflammation, cancer, and viral infection. There are 29 very diverse family members of TNFRSF reported in humans: 22 are type I transmembrane receptors (single pass with the N terminus on extracellular side of the cell membrane) and have a clear signal peptide; the remaining 7 members are either type III transmembrane receptors (single pass with the N terminus on extracellular side of the membrane but no signal sequence; TNFR13B, TNFR13C, TNFR17, and XEDAR), or attached to the membrane via a glycosylphosphatidylinositol (GPI) linker (TNFR10C), or secreted as soluble receptors (TNFR11B and TNFR6B). All TNFRs contain relatively short cysteine-rich domains (CRDs) in the ectodomain, and are involved in interaction with the TNF homology domain (THD) of their ligands. TNFRs often have multiple CRDs (between one and six), with the most frequent configurations of three or four copies; most CRDs possess three disulfide bridges, but could have between one and four. Localized or genome-wide duplication and evolution of the TNFRSF members appear to have paralleled the emergence of the adaptive immune system; teleosts (i.e. ray-finned, bony fish), which possess an immune system with B and T cells, possess primary and secondary lymphoid organs, and are capable of adaptive responses to pathogens also display several characteristics that are different from the mammalian immune system, making teleost TNFSF orthologs and paralogs of interest to better understand immune system evolution and the immunological pathways elicited to pathogens.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  38 KKKVEDCKMNGGTPTCAPCTEGKEYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVRC 117
Cdd:cd10579    29 TRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKNCTRTQNTKCRCKSNFFCNSSPCEHCDPC 108

                          90       100
                  ....*....|....*....|.
gi 1720394530 118 ASCEHGTLEPCTATSNTNCRK 138
Cdd:cd10579   109 TTCEHGIIEECTPTSNTKCKK 129

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as fas cell surface death receptor (Fas); TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A) contains a death domain and plays a central role in the physiological regulation of programmed cell death. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Of the several alternatively spliced transcript variants, some are candidates for nonsense-mediated mRNA decay (NMD). Isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  38 KKKVEDCKMNGGTPTCAPCTEGKEYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVRC 117
Cdd:cd10579    29 TRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKNCTRTQNTKCRCKSNFFCNSSPCEHCDPC 108

                          90       100
                  ....*....|....*....|.
gi 1720394530 118 ASCEHGTLEPCTATSNTNCRK 138
Cdd:cd10579   109 TTCEHGIIEECTPTSNTKCKK 129

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  195 SLSKYIPRIAEDM-TIQEAKKFARENNIKEGKIDEIMHDSIQDTAEQKVQLLLCWYQSHGKSDAYQDLIKGLKKAECRRT 273
Cdd:smart00005   2 ELTRQKLAKLLDHpLGLDWRELARKLGLSEADIDQIRTEAPRDLAEQSVQLLRLWEQREGKNATLGTLLEALRKMGRDDA 81

                   ....*..
gi 1720394530  274 LDKFQDM 280
Cdd:smart00005  82 VELLRSE 88

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1720394530 100 CKPDFYCDSPGCEHCVRCASCEHGT--LEPCTATSNTNC 136
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQvvVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as fas cell surface death receptor (Fas); TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A) contains a death domain and plays a central role in the physiological regulation of programmed cell death. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Of the several alternatively spliced transcript variants, some are candidates for nonsense-mediated mRNA decay (NMD). Isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  38 KKKVEDCKMNGGTPTCAPCTEGKEYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVRC 117
Cdd:cd10579    29 TRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKNCTRTQNTKCRCKSNFFCNSSPCEHCDPC 108

                          90       100
                  ....*....|....*....|.
gi 1720394530 118 ASCEHGTLEPCTATSNTNCRK 138
Cdd:cd10579   109 TTCEHGIIEECTPTSNTKCKK 129

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  195 SLSKYIPRIAEDM-TIQEAKKFARENNIKEGKIDEIMHDSIQDTAEQKVQLLLCWYQSHGKSDAYQDLIKGLKKAECRRT 273
Cdd:smart00005   2 ELTRQKLAKLLDHpLGLDWRELARKLGLSEADIDQIRTEAPRDLAEQSVQLLRLWEQREGKNATLGTLLEALRKMGRDDA 81

                   ....*..
gi 1720394530  274 LDKFQDM 280
Cdd:smart00005  82 VELLRSE 88

Tumor necrosis factor receptor superfamily member 26 (TNFRSF26), also known as tumor necrosis factor receptor homolog 3 (TNFRH3); TNFRSF26 (also known as tumor necrosis factor receptor homolog 3 (TNFRH3) or TNFRSF24) is predominantly expressed in embryos and lymphoid cell types, along with its closely related TNFRSF22 and TNFRSF23 orthologs, and is developmentally regulated. Unlike TNFRSF22/23, TNFRSF26 does not serve as a TRAIL decoy receptor; it remains an orphan receptor.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  42 EDCKMNGGTPTCAPCTEGKeYMDKNHYADKCRRCTLCDEEHglEVETNCTLTQNTKCKCKPDFYCDSPGC-EHCVRCASC 120
Cdd:cd15837    24 EPCQENHGVGECAPCEPGT-FTAHPNGETSCFPCSQCRDDQ--EVVAECSATSDRQCQCKQGHFYCDENClESCFRCSRC 100

                          90
                  ....*....|....*...
gi 1720394530 121 EHG--TLEPCTATSNTNC 136
Cdd:cd15837   101 PGGrvVLQPCNATRDTVC 118

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in teleosts; also known as TNFR1; This subfamily of TNFRSF1 ((also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) is found in teleosts. It binds TNF-alpha, through the death domain (DD), and activates NF-kappaB, mediates apoptosis and activates signaling pathways controlling inflammatory, immune, and stress responses. It mediates signal transduction by interacting with antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRAF2 and TRADD that play regulatory roles. The human genetic disorder called tumor necrosis factor associated periodic syndrome (TRAPS), or periodic fever syndrome, is associated with germline mutations of the extracellular domains of this receptor, possibly due to impaired receptor clearance. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. Knockout studies in zebrafish embryos have shown that a signaling balance between TNFRSF1A and TNFRSF1B is required for endothelial cell integrity. TNFRSF1A signals apoptosis through caspase-8, whereas TNFRSF1B signals survival via NF-kappaB in endothelial cells. Thus, this apoptotic pathway seems to be evolutionarily conserved, as TNFalpha promotes apoptosis of human endothelial cells and triggers caspase-2 and P53 activation in these cells via TNFRSF1A.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  39 KKVEDCKMNGGTPTCAPCTEGkEYMDKNHYADKCRRCTLCDEEHGLEVeTNCTLTQNTKCKCKPDFY---CDSPGCEhCV 115
Cdd:cd15834    22 KLKEECTAPGERSQCTPCPEG-TYLEQINYSPNCRRCTLCKVKNEEEV-SPCKKSSNTVCRCKKGYYksrIDSETRE-CL 98

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1720394530 116 RCASCEHGTLE--PCTATSNTNCRKQSPRNR 144
Cdd:cd15834    99 KCKTCGPGEIEiqPCTPESNTVCECKDNYYR 129

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14) in teleost; also known as herpes virus entry mediator (HVEM); This subfamily of TNFRSF14 (also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR, TR2) is found in teleosts, many of which are as yet uncharacterized. It regulates T-cell immune responses by activating inflammatory as well as inhibitory signaling pathways. HVEM acts as a receptor for the canonical TNF-related ligand LIGHT (lymphotoxin-like), which exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM. It also acts as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules, thus, creating a functionally diverse set of intrinsic and bidirectional signaling pathways. HVEM is highly expressed in the gut epithelium. Genome-wide association studies have shown that HVEM is an inflammatory bowel disease (IBD) risk gene, suggesting that HVEM could have a regulatory role influencing the regulation of epithelial barrier, host defense, and the microbiota. Mouse models have revealed that HVEM is involved in colitis pathogenesis, mucosal host defense, and epithelial immunity, thus acting as a mucosal gatekeeper with multiple regulatory functions in the mucosa. HVEM plays a critical role in both tumor progression and resistance to antitumor immune responses, possibly through direct and indirect mechanisms. It is known to be expressed in several human malignancies, including esophageal squamous cell carcinoma, follicular lymphoma, and melanoma. HVEM network may therefore be an attractive target for drug intervention. In Asian seabass, the up-regulation of differentially expressed TNFRSF14 gene has been observed.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  42 EDCKMNGGTpTCAPCTEGkEYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVrcASCE 121
Cdd:cd13405    24 RHCTEDTST-SCVPCPDG-TYMDEPNGLEKCFPCTNCDPGFGLRVKQGCTYTSDTVCEPLEGFYCIDSTKDGCS--AAQR 99

                  .
gi 1720394530 122 H 122
Cdd:cd13405   100 H 100

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), also known as TNFR1; TNFRSF1A (also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) binds TNF-alpha, through the death domain (DD), and activates NF-kappaB, mediates apoptosis and activates signaling pathways controlling inflammatory, immune, and stress responses. It mediates signal transduction by interacting with antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRAF2 and TRADD that play regulatory roles. The human genetic disorder called tumor necrosis factor associated periodic syndrome (TRAPS), or periodic fever syndrome, is associated with germline mutations of the extracellular domains of this receptor, possibly due to impaired receptor clearance. TNFRSF1A polymorphisms rs1800693 and rs4149584 are associated with elevated risk of multiple sclerosis. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. Patients with idiopathic recurrent acute pericarditis (IRAP), presumed to be an autoimmune process, have also been shown to carry rare mutations (R104Q and D12E) in the TNFRSF1A gene.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  40 KVEDCKMNGGTPTCAPCTEGKeYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPG-CEHCVRCA 118
Cdd:cd10576    24 LYNDCPGPGQDTVCRECENGT-FTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDTVCGCRKNQYQHYWSsLFQCKNCS 102

                          90       100
                  ....*....|....*....|
gi 1720394530 119 SCEHGTL-EPCTATSNTNCR 137
Cdd:cd10576   103 LCLNGTIrQPCQEKQDTICT 122

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as p75 neurotrophin receptor (p75NTR) or CD271; TNFRSF16 (also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75(NTR)), CD271, Gp80-LNGFR) is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways. It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex. On melanoma cell, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens. It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation. p75(NTR) is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia. It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  53 CAPCTEGKEYMDKNHYADKCRRCTLCdeEHGLEVETNCTLTQNTKCKCKPDFYCDSPGcEHCVRCASCE--HGTLEPCTA 130
Cdd:cd13416    35 CEPCLDGVTFSDVVSHTEPCQPCTRC--PGLMSMRAPCTATHDTVCECAYGYYLDEDS-GTCEPCTVCPpgQGVVQSCGP 111

                  ....*...
gi 1720394530 131 TSNTNCRK 138
Cdd:cd13416   112 NQDTVCEA 119

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40; TNFRSF5 (commonly known as CD40 and also as CDW40, p50, Bp50) is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  38 KKKVEDCKMNGGTpTCAPCTEGkEYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVRC 117
Cdd:cd13407    20 QKLVSDCTEATDT-ECLPCEEG-EFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDTTCTCQEGQHCTSEACETCALH 97

                          90       100
                  ....*....|....*....|.
gi 1720394530 118 ASCE--HGTLEPCTATSNTNC 136
Cdd:cd13407    98 TSCKpgFGVKQIATGVSDTIC 118

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5) in teleosts; also known as CD40; TNFRSF5 (commonly known as CD40 and also as CDW40, p50, Bp50) is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection. Salmon CD40 and CD40L are widely expressed, particularly in immune tissues, and their importance for the immune response is indicated by their relatively high expression in salmon lymphoid organs and gills.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1720394530  51 PTCAPCTEGkEYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVRCASCEHG 123
Cdd:cd13422    32 PQCQPCGED-EYQDKYTKENKCKRQPYCDPNKNFEISVNKSKTSRSVCKCKPGFHCSSEECLTCVPHTTCGPG 103

tumor necrosis factor receptor superfamily member 25 (TNFRSF25), also known as death receptor 3 (DR3); TNFRSF25 (also known as death receptor 3 (DR3), death domain receptor 3 (DDR3), apoptosis-mediating receptor, lymphocyte associated receptor of death (LARD), apoptosis inducing receptor (AIR), APO-3, translocating chain-association membrane protein (TRAMP), WSL-1, WSL-LR or TNFRSF12) is preferentially expressed in thymocytes and lymphocytes, and may play a role in regulating lymphocyte homeostasis. It has been detected in lymphocyte-rich tissues such as colon, intestine, thymus and spleen, as well as in the prostate. Various death domain containing adaptor proteins mediate the signal transduction of this receptor; it activates nuclear factor kappa-B (NFkB) and induces cell apoptosis by associating with TNFRSF1A-associated via death domain (TRADD), which is known to mediate signal transduction of tumor necrosis factor receptors. DR3 associates with tumor necrosis factor (TNF)-like cytokine 1A (TL1A also known as TNFSF15) on activated lymphocytes and induces pro-inflammatory signals; TL1A also binds decoy receptor DcR3 (also known as TNFRSF6B). DR3/DcR3/TL1A expression is increased in both serum and inflamed tissues in autoimmune diseases such as in several autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), allergic asthma, experimental autoimmune encephalomyelitis, type 1 diabetes, ankylosing spondylitis (AS), and primary biliary cirrhosis (PBC), making modulation of TL1A-DR3 interaction a potential therapeutic target.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  44 CKMNGGTPTCAPCTEGKEYMDKNHYADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFY-------CDSPGCEHCVR 116
Cdd:cd13420    30 CTEPCGNSTCLPCPRGTFLARENHHKTDCTRCQACDEQASQVALENCSAVSDTHCGCESGWFvecsvkdCVSSSPFSCKP 109

                  ....
gi 1720394530 117 CASC 120
Cdd:cd13420   110 CLDC 113

Tumor necrosis factor receptor superfamily member 6B (TNFRSF6B), also known as decoy receptor 3 (DcR3); The subfamily TNFRSF6B is also known as decoy receptor 3 (DcR3), M68, or TR6. This protein is a soluble receptor without death domain and cytoplasmic domain, and secreted by cells. It acts as a decoy receptor that competes with death receptors for ligand binding. It is a pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases, and cancer. Over-expression of this gene has been noted in several cancers, including pancreatic carcinoma, and gastrointestinal tract tumors. It can neutralize the biological effects of three tumor necrosis factor superfamily (TNFSF) members: TNFSF6 (Fas ligand/FasL/CD95L) and TNFSF14 (LIGHT) which are both involved in apoptosis and inflammation, and TNFSF15 (TNF-like molecule 1A/TL1A), which is a T cell co-stimulator and involved in gut inflammation. DcR3 is a novel inflammatory marker; higher DcR3 levels strongly correlate with inflammation and independently predict cardiovascular and all-cause mortality in chronic kidney disease (CKD) patients on hemodialysis. Increased synovial inflammatory cells infiltration in rheumatoid arthritis and ankylosing spondylitis is also associated with the elevated DcR3 expression. In cartilaginous fish, mRNA expression of DcR3 in the thymus and leydig, which are the representative lymphoid tissues of elasmobranchs, suggests that DcR3 may act as a modulator in the immune system. Interestingly, in banded dogfish (Triakis scyllia), DcR3 mRNA is strongly expressed in the gill, compared with human expression in the normal lung; both are respiratory organs, suggesting potential relevance of DcR3 to respiratory function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  52 TCAPCTEgKEYMDKNHYADKCRRCTLCDEEHGLEVETnCTLTQNTKCKCKPDFYCDSpgcEHCVRCASCE--HGTLEPCT 129
Cdd:cd10575    36 VCGPCPD-LHYTQFWNYLEKCRYCNVFCTERQVEKRQ-CNATHNRVCECKPGYYMEH---GFCLRHSSCPpgEGVIKLGT 110

                  ....*....
gi 1720394530 130 ATSNTNCRK 138
Cdd:cd10575   111 PYSDTQCEP 119

Tumor necrosis factor receptor superfamily member 7 (TNFRSF7), also known as CD27; TNFRSF7 (also known as CD27, T14, S152, Tp55, S152, LPFS2) has a key role in the generation of immunological memory via effects on T-cell expansion and survival, and B cell development. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. CD27 transduces signals that lead to the activation of NF-kappaB and MAPK8/JNK, and mediates the signaling process through adaptor proteins TRAF2 and TRAF5. CD27-binding protein (SIVA), a pro-apoptotic protein, can bind to CD27 and may play an important role in the apoptosis induced by this receptor. The potential role of the CD27/CD70 pathway in the course of inflammatory diseases, such as arthritis, and inflammatory bowel disease, suggests that CD70 may be a target for immune intervention. The expression of CD27 and CD44 molecules correlates with the differentiation stage of B cell precursors and has been shown to have a biological significance in acute lymphoblastic leukemia.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720394530  41 VEDCKMNGGTPTCAPCTEGKEYMDKNHYADKCRRCTLCDEEHGLEvetNCTLTQNTKCKCKPDFYCDSPGCEHC 114
Cdd:cd13408    47 VKDCDQHGKAAQCDPCIPGVSFSPDHHARPHCESCRHCNSGLLIR---NCTITANTECACPKGWQCRDKECTEC 117

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1720394530 100 CKPDFYCDSPGCEHCVRCASCEHGT--LEPCTATSNTNC 136
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQvvVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), also known as TNFR2; TNFRSF1B (also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) binds TNF-alpha, but lacks the death domain (DD) that is associated with the cytoplasmic domain of TNFRSF1A (TNFR1). It is inducible and expressed exclusively by oligodendrocytes, astrocytes, T cells, thymocytes, myocytes, endothelial cells, and in human mesenchymal stem cells. TNFRSF1B protects oligodendrocyte progenitor cells (OLGs) against oxidative stress, and induces the up-regulation of cell survival genes. While pro-inflammatory and pathogen-clearing activities of TNF are mediated mainly through activation of TNFRSF1A, a strong activator of NF-kappaB, TNFRSF1B is more responsible for suppression of inflammation. Although the affinities of both receptors for soluble TNF are similar, TNFRSF1B is sometimes more abundantly expressed and thought to associate with TNF, thereby increasing its concentration near TNFRSF1A receptors, and making TNF available to activate TNFRSF1A (a ligand-passing mechanism).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720394530  53 CAPCTEGKEYMDKNHYadkcRRCTLCDEEHGLE-VET-NCTLTQNTKCKCKPDFYCDS---PGCEHCVRCASCE--HGTL 125
Cdd:cd10577    37 CAPCEESTYTQLWNWV----PECLSCSSPCSSDqVETqACTRQQNRICSCKPGWYCVLklqEGCRQCRPLKKCGpgFGVA 112

                          90
                  ....*....|....*.
gi 1720394530 126 EPCTATSNTNCRKQSP 141
Cdd:cd10577   113 RPGTASSDVECKPCAP 128

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14), also known as herpes virus entry mediator (HVEM); TNFRSF14 (also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR, TR2) regulates T-cell immune responses by activating inflammatory, as well as inhibitory signaling pathways. HVEM acts as a receptor for the canonical TNF-related ligand LIGHT (lymphotoxin-like), which exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM. It also acts as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules, thus, creating a functionally diverse set of intrinsic and bidirectional signaling pathways. HVEM is highly expressed in the gut epithelium. Genome-wide association studies have shown that Hvem is an inflammatory bowel disease (IBD) risk gene, suggesting that HVEM could have a regulatory role influencing the regulation of epithelial barrier, host defense, and the microbiota. Mouse models have revealed that HVEM is involved in colitis pathogenesis, mucosal host defense, and epithelial immunity, thus acting as a mucosal gatekeeper with multiple regulatory functions in the mucosa. HVEM plays a critical role in both tumor progression and resistance to antitumor immune responses, possibly through direct and indirect mechanisms. It is known to be expressed in several human malignancies, including esophageal squamous cell carcinoma, follicular lymphoma and melanoma. HVEM network may therefore be an attractive target for drug intervention.

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gi 1720394530  52 TCAPCTEGKEYMDKNHyADKCRRCTLCDEEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVRCAS 119
Cdd:cd10582    33 VCEPCPPGTYTAHLNG-LSKCLQCRVCDPAMGLVTRRNCSSTENTVCGCIPGHFCSAQDGDHCVECVP 99

Tumor necrosis factor receptor superfamily (TNFRSF); Members of TNFR superfamily (TNFRSF) interactions with TNF superfamily (TNFSF) ligands (TNFL) control key cellular processes such as differentiation, proliferation, apoptosis, and cell growth. Dysregulation of these pathways has been shown to result in a wide range of pathological conditions, including autoimmune diseases, inflammation, cancer, and viral infection. There are 29 very diverse family members of TNFRSF reported in humans: 22 are type I transmembrane receptors (single pass with the N terminus on extracellular side of the cell membrane) and have a clear signal peptide; the remaining 7 members are either type III transmembrane receptors (single pass with the N terminus on extracellular side of the membrane but no signal sequence; TNFR13B, TNFR13C, TNFR17, and XEDAR), or attached to the membrane via a glycosylphosphatidylinositol (GPI) linker (TNFR10C), or secreted as soluble receptors (TNFR11B and TNFR6B). All TNFRs contain relatively short cysteine-rich domains (CRDs) in the ectodomain, and are involved in interaction with the TNF homology domain (THD) of their ligands. TNFRs often have multiple CRDs (between one and six), with the most frequent configurations of three or four copies; most CRDs possess three disulfide bridges, but could have between one and four. Localized or genome-wide duplication and evolution of the TNFRSF members appear to have paralleled the emergence of the adaptive immune system; teleosts (i.e. ray-finned, bony fish), which possess an immune system with B and T cells, possess primary and secondary lymphoid organs, and are capable of adaptive responses to pathogens also display several characteristics that are different from the mammalian immune system, making teleost TNFSF orthologs and paralogs of interest to better understand immune system evolution and the immunological pathways elicited to pathogens.

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gi 1720394530  71 KCRRCtlcdeEHGLEVETNCTLTQNTKCK-CKPDFYCDSPG-CEHCVRCASCEHGTLE---PCTATSNTNCR 137
Cdd:cd00185     1 CCQRC-----PPGEYLSSDCTATTDTVCSpCPPGTYSESWNsLSKCLPCTTCGGGNQVektPCTATDNRCCT 67

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137; TNFRSF9 (also known as CD137, ILA, 4-1BB) plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors.

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gi 1720394530  50 TPTCAPCTEGK-EYMDKNHYADKCRRCtlcdeEHGLEVETNCTLTQNTKCKCKPDFYCDSPGCEHCVrcASCEHG 123
Cdd:cd13410    20 DQTCIPCPPNSfSSTGGQQTCDICRKC-----EGVFRTKKPCSSTSNAECECVPGFHCLGPGCSMCE--PDCKQG 87

Tumor necrosis factor receptor superfamily member 4 (TNFRSF4), also known as CD134 or OXO40; TNFRSF4 (also known as OX40, ACT35, CD134, IMD16, TXGP1L) activates NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. It also promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. It is primarily expressed on activated CD4+ and CD8+ T cells, where it is transiently expressed and upregulated on the most recently antigen-activated T cells within inflammatory lesions. This makes it an attractive target to modulate immune responses, i.e. TNFRSF4 (OX40) blocking agents to inhibit adverse inflammation or agonists to enhance immune responses. An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Some single nucleotide polymorphisms (SNPs) of its natural ligand OX40 ligand (OX40L, CD252), which is also found on activated T cells, have been associated with systemic lupus erythematosus.

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gi 1720394530  83 GLEVETNCTLTQNTKC-KCKPDFYCDSPGCEHCVRCASCEHGT----LEPCTATSNTNCR 137
Cdd:cd13406    21 GEGMESRCTGTQDTVCsPCEPGFYNEAVNYEPCKPCTQCNQRSgseeKQKCTKTSDTVCR 80