title: Tumor necrosis factor (TNF) interferes with insulin signaling through the p55 TNF receptor death domain.
abstract: Tumor necrosis factor (TNF) contributes to insulin resistance by binding to the 55kDa TNF receptor (TNF-R55), resulting in serine phosphorylation of proteins such as insulin receptor (IR) substrate (IRS)-1, followed by reduced tyrosine phosphorylation of IRS-1 through the IR and, thereby, diminished IR signal transduction. Through independent receptor domains, TNF-R55 activates a neutral (N-SMase) and an acid sphingomyelinase (A-SMase), that both generate the sphingolipid ceramide. Multiple candidate kinases have been identified that serine-phosphorylate IRS-1 in response to TNF or ceramide. However, due to the fact that the receptor domain of TNF-R55 mediating inhibition of the IR has not been mapped, it is currently unknown whether TNF exerts these effects with participation of N-SMase or A-SMase. Here, we identify the death domain of TNF-R55 as responsible for the inhibitory effects of TNF on tyrosine phosphorylation of IRS-1, implicating ceramide generated by A-SMase as a downstream mediator of inhibition of IR signaling.
authors.affiliation: Institut für Immunologie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Michaelisstr. 5, 24105 Kiel, Germany.
authors.forename: Susan-Beatrice
authors.initials: SB
authors.lastname: Csehi
authors.forename: Sabine
authors.initials: S
authors.lastname: Mathieu
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seifert
authors.forename: Arne
authors.initials: A
authors.lastname: Lange
authors.forename: Margit
authors.initials: M
authors.lastname: Zweyer
authors.forename: Anton
authors.initials: A
authors.lastname: Wernig
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism; D015925:Cryopreservation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry
chemical_list: D002518:Ceramides; D007328:Insulin; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase