TNFR1 membrane reorganization promotes distinct modes of TNFα signaling

• Published in: Science signaling Vol. 12; no. 592
• Main Authors: Morton, Penny E, Perrin, Camille, Levitt, James, Matthews, Daniel R, Marsh, Richard J, Pike, Rosemary, McMillan, David, Maloney, Alison, Poland, Simon, Ameer-Beg, Simon, Parsons, Maddy
• Format: Journal Article
• Language: English
• Published: United States 30-07-2019
• Subjects: HeLa Cells; Humans; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; MAP Kinase Kinase Kinase 1 - genetics; MAP Kinase Kinase Kinase 1 - metabolism; MAP Kinase Signaling System; NF-kappa B - genetics; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.aaw2418

Signaling by the ubiquitously expressed tumor necrosis factor receptor 1 (TNFR1) after ligand binding plays an essential role in determining whether cells exhibit survival or death. TNFR1 forms distinct signaling complexes that initiate gene expression programs downstream of the transcriptional regulators NFκB and AP-1 and promote different functional outcomes, such as inflammation, apoptosis, and necroptosis. Here, we investigated the ways in which TNFR1 was organized at the plasma membrane at the nanoscale level to elicit different signaling outcomes. We confirmed that TNFR1 forms preassembled clusters at the plasma membrane of adherent cells in the absence of ligand. After trimeric TNFα binding, TNFR1 clusters underwent a conformational change, which promoted lateral mobility, their association with the kinase MEKK1, and activation of the JNK/p38/NFκB pathway. These phenotypes required a minimum of two TNFR1-TNFα contact sites; fewer binding sites resulted in activation of NFκB but not JNK and p38. These data suggest that distinct modes of TNFR1 signaling depend on nanoscale changes in receptor organization.