Research ArticleBiochemistry

TNFR1 membrane reorganization promotes distinct modes of TNFα signaling

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Science Signaling  30 Jul 2019:
Vol. 12, Issue 592, eaaw2418
DOI: 10.1126/scisignal.aaw2418

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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.

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