title: Apparently normal tumor necrosis factor receptor 1 signaling in the absence of the silencer of death domains.
abstract: The silencer of death domains (SODD) has been proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 (TNFR1) in the absence of ligand. Besides TNFR1, death receptor 3 (DR3), Hsp70/Hsc70, and Bcl-2 have been characterized as binding partners of SODD. In order to investigate the in vivo role of SODD, we generated mice congenitally deficient in expression of the sodd gene. No spontaneous inflammatory infiltrations were observed in any organ of these mice. Consistent with this finding, in the absence of SODD no alteration in the activation patterns of nuclear factor kappaB (NF-kappaB), stress kinases, or ERK1 or -2 was observed after stimulation with tumor necrosis factor (TNF). Activation of NF-kappaB by DR3 was also unchanged. The extents of DR3- and TNF-induced apoptosis were comparable in gene-deficient and wild-type cells. Protection of cells against heat shock as mediated by the Hsp70 system and against staurosporine-induced apoptosis was independent of SODD. Furthermore, resistance to high-dose lipopolysaccharide (LPS) injections, LPS-D-GalN injections, and infection with listeriae was similar in wild-type and gene-deficient mice. In conclusion, our data do not support the concept of a unique, nonredundant role of SODD for the functions of TNFR1, Hsp70, and DR3.
authors.affiliation: Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, D-81675 Munich, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Endres
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
authors.forename: Inge
authors.initials: I
authors.lastname: Brosch
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation; D005260:Female; D020022:Genetic Predisposition to Disease; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018869:Heat-Shock Response / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D008087:Listeria / Q000276:immunology; D016131:Lymphocyte Subsets; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D012016:Reference Values; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C116906:BAG4 protein, human; C487979:Bag4 protein, mouse; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; C506033:TNFRSF25 protein, human; C506034:Tnfrsf25 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019311:Staurosporine