title: The tumor necrosis factor receptor stalk regions define responsiveness to soluble versus membrane-bound ligand.
abstract: The family of tumor necrosis factor receptors (TNFRs) and their ligands form a regulatory signaling network that controls immune responses. Various members of this receptor family respond differently to the soluble and membrane-bound forms of their respective ligands. However, the determining factors and underlying molecular mechanisms of this diversity are not yet understood. Using an established system of chimeric TNFRs and novel ligand variants mimicking the bioactivity of membrane-bound TNF (mTNF), we demonstrate that the membrane-proximal extracellular stalk regions of TNFR1 and TNFR2 are crucial in controlling responsiveness to soluble TNF (sTNF). We show that the stalk region of TNFR2, in contrast to the corresponding part of TNFR1, efficiently inhibits both the receptor's enrichment/clustering in particular cell membrane regions and ligand-independent homotypic receptor preassembly, thereby preventing sTNF-induced, but not mTNF-induced, signaling. Thus, the stalk regions of the two TNFRs not only have implications for additional TNFR family members, but also provide potential targets for therapeutic intervention.
authors.affiliation: Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Richter
authors.forename: Sylvia
authors.initials: S
authors.lastname: Messerschmidt
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Holeiter
authors.forename: Jessica
authors.initials: J
authors.lastname: Tepperink
authors.forename: Sylvia
authors.initials: S
authors.lastname: Osswald
authors.forename: Andrea
authors.initials: A
authors.lastname: Zappe
authors.forename: Marcus
authors.initials: M
authors.lastname: Branschädel
authors.forename: Verena
authors.initials: V
authors.lastname: Boschert
authors.forename: Derek A
authors.initials: DA
authors.lastname: Mann
authors.forename: Peter
authors.initials: P
authors.lastname: Scheurich
authors.forename: Anja
authors.initials: A
authors.lastname: Krippner-Heidenreich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006031:Glycosylation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha