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The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

Lookup NU author(s): Christine Richter, Professor Derek Mann, Dr Anja Krippner-Heidenreich


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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.

Publication metadata

Author(s): Richter C, Messerschmidt S, Holeiter G, Tepperink J, Osswald S, Zappe A, Bransch├Ądel M, Boschert V, Mann DA, Scheurich P, Krippner-Heidenreich A

Publication type: Article

Publication status: Published

Journal: Molecular and Cellular Biology

Year: 2012

Volume: 32

Issue: 13

Pages: 2515-2529

Print publication date: 30/04/2012

ISSN (print): 0270-7306

ISSN (electronic): 1098-5549

Publisher: American Society for Microbiology


DOI: 10.1128/MCB.06458-11


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Funder referenceFunder name
087961Wellcome Trust
KR3307/1-1German Research Foundation (DFG)
SFB 495German Research Foundation (DFG)