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 148233384  14 CTNQQYWDSLLCQCIPCSLMCGHSAVRRCTALCESAVCNRRAGFYYDELVKKCISCSTVCGQHPKQCDAACGGSL----- 88
Cdd:cd13415    1 CPDEQYWDSLVGQCISCSLICSRRSVRTCAAFCKSMSCNKEQGKYYDHLLKDCISCASVCGQHPKQCAPFCENKLrsrvn 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384  89 -------------------LASRPPPAALVSASPPAAALeqkVCVEQEPWLVVYLLLGLCLCALVCSLVLG-WTHLRKKG 148
Cdd:cd13415   81 lppplrrqqsgetetrsdnSGRYQGSEHRGSEAGPALPG---PKLSADQLLLVYCTLGLCLCAIVCCFLVAvACFLRRRG 157

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384 149 EVGSCQASTGTCHCREDPAKDHLVEAGSVGEGStgskaSEPVETCGFCFPGHGSAVQETK 208
Cdd:cd13415  158 EPLSCQPAAGPCRLRAKSSKDRLVEAGSVGDGV-----PEPVETCSFCFPEHRSPTQESA 212

Tumor necrosis factor receptor superfamily member 13B (TNFRSF13B), also known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI); TNFRSF13B (also known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), CVID, RYZN, CD267, CVID2, TNFRSF14B) is mainly expressed on B cells and binds strongly to B cell activating factor (BAFF) and weakly to a proliferation-inducing ligand (APRIL). TACI-APRIL interactions induce B-cell differentiation, whereas TACI-BAFF ligation negatively regulates B-cell functions. In humans, TACI is expressed on memory B cells and TACI mutations are detected in 8-10% of common variable immunodeficiency (CVID) patients, making it the most frequently mutated gene for the disease. Coexisting morbidities in CVID include bronchiectasis, autoimmunity, and malignancies. However, TNFRSF13B/TACI defects alone do not result in CVID but may also be found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies. Over-expression of TACI has been detected in multiple myeloma and thyroid carcinoma; correlative analyses suggest that TACI expression is a useful prognostic marker for lymphoma.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384  14 CTNQQYWDSLLCQCIPCSLMCGHSAVRRCTALCESAVCNRRAGFYYDELVKKCISCSTVCGQHPKQCDAACGGSL----- 88
Cdd:cd13415    1 CPDEQYWDSLVGQCISCSLICSRRSVRTCAAFCKSMSCNKEQGKYYDHLLKDCISCASVCGQHPKQCAPFCENKLrsrvn 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384  89 -------------------LASRPPPAALVSASPPAAALeqkVCVEQEPWLVVYLLLGLCLCALVCSLVLG-WTHLRKKG 148
Cdd:cd13415   81 lppplrrqqsgetetrsdnSGRYQGSEHRGSEAGPALPG---PKLSADQLLLVYCTLGLCLCAIVCCFLVAvACFLRRRG 157

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384 149 EVGSCQASTGTCHCREDPAKDHLVEAGSVGEGStgskaSEPVETCGFCFPGHGSAVQETK 208
Cdd:cd13415  158 EPLSCQPAAGPCRLRAKSSKDRLVEAGSVGDGV-----PEPVETCSFCFPEHRSPTQESA 212

Tumor necrosis factor receptor superfamily member 13B (TNFRSF13B), also known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI); TNFRSF13B (also known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), CVID, RYZN, CD267, CVID2, TNFRSF14B) is mainly expressed on B cells and binds strongly to B cell activating factor (BAFF) and weakly to a proliferation-inducing ligand (APRIL). TACI-APRIL interactions induce B-cell differentiation, whereas TACI-BAFF ligation negatively regulates B-cell functions. In humans, TACI is expressed on memory B cells and TACI mutations are detected in 8-10% of common variable immunodeficiency (CVID) patients, making it the most frequently mutated gene for the disease. Coexisting morbidities in CVID include bronchiectasis, autoimmunity, and malignancies. However, TNFRSF13B/TACI defects alone do not result in CVID but may also be found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies. Over-expression of TACI has been detected in multiple myeloma and thyroid carcinoma; correlative analyses suggest that TACI expression is a useful prognostic marker for lymphoma.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384  14 CTNQQYWDSLLCQCIPCSLMCGHSAVRRCTALCESAVCNRRAGFYYDELVKKCISCSTVCGQHPKQCDAACGGSL----- 88
Cdd:cd13415    1 CPDEQYWDSLVGQCISCSLICSRRSVRTCAAFCKSMSCNKEQGKYYDHLLKDCISCASVCGQHPKQCAPFCENKLrsrvn 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384  89 -------------------LASRPPPAALVSASPPAAALeqkVCVEQEPWLVVYLLLGLCLCALVCSLVLG-WTHLRKKG 148
Cdd:cd13415   81 lppplrrqqsgetetrsdnSGRYQGSEHRGSEAGPALPG---PKLSADQLLLVYCTLGLCLCAIVCCFLVAvACFLRRRG 157

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 148233384 149 EVGSCQASTGTCHCREDPAKDHLVEAGSVGEGStgskaSEPVETCGFCFPGHGSAVQETK 208
Cdd:cd13415  158 EPLSCQPAAGPCRLRAKSSKDRLVEAGSVGDGV-----PEPVETCSFCFPEHRSPTQESA 212