TY - JOUR
T1 - The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand
AU - Richter, Christine
AU - Messerschmidt, Sylvia
AU - Holeiter, Gerlinde
AU - Tepperink, Jessica
AU - Osswald, Sylvia
AU - Zappe, Andrea
AU - Branschädel, Marcus
AU - Boschert, Verena
AU - Mann, Derek A.
AU - Scheurich, Peter
AU - Krippner-Heidenreicha, Anja
PY - 2012/7
Y1 - 2012/7
N2 - 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 membranebound 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 ligandindependent 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.
AB - 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 membranebound 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 ligandindependent 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.
UR - http://www.scopus.com/inward/record.url?scp=84864018997&partnerID=8YFLogxK
U2 - 10.1128/MCB.06458-11
DO - 10.1128/MCB.06458-11
M3 - Article
C2 - 22547679
AN - SCOPUS:84864018997
SN - 0270-7306
VL - 32
SP - 2515
EP - 2529
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 13
ER -