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TNFR1 membrane reorganization promotes distinct modes of TNFα signaling

Nanoscale reorganization of TNFR1 within the plasma membrane promotes the activation of distinct signaling pathways. Organizing TNFR1 signaling The inflammatory cytokine tumor necrosis factor–α (TNFα) stimulates both cell death and survival by activating its ubiquitously expressed membrane receptor, TNFR1. Morton et al. used various microscopy techniques to investigate TNFR1 membrane organization. In resting cells, TNFR1 was found within clusters that required its cytoplasmic tail. After TNFα binding, TNFR1 clusters were denser and moved within the membrane more rapidly, which correlated with the activation of specific downstream pathways and physical association with the kinase MEKK1. Experiments with engineered ligands that could only bind a specific number of TNFR1 molecules suggested that engagement of two receptors was sufficient for signaling but that trimeric interactions were necessary for extracellular conformational changes in TNFR1. These findings suggest how membrane organization alters TNFR1 signaling, insights that may direct the development of TNF-targeted therapeutics with increased potency. 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.