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Single-molecule imaging reveals the oligomeric state of functional TNFα-induced plasma membrane TNFR1 clusters in cells

Karathanasis, C., Medler, J., Fricke, F., Smith, S., Malkusch, S., Widera, D. ORCID: https://orcid.org/0000-0003-1686-130X, Fulda, S., Wajant, H., van Wijk, S. J. L., Dikic, I. and Heilemann, M. (2020) Single-molecule imaging reveals the oligomeric state of functional TNFα-induced plasma membrane TNFR1 clusters in cells. Science Signaling, 13 (614). eaax5647. ISSN 1937-9145

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To link to this item DOI: 10.1126/scisignal.aax5647

Abstract/Summary

Ligand-induced tumor necrosis factor receptor 1 (TNFR1) activation controls NF-ĸB (nuclear factor kappa-light-chain-enhancer of activated B-cells) signaling, cell proliferation, programmed cell death, and survival, and is crucially involved in inflammation, autoimmune disorders, and cancer progression. Despite the relevance of TNFR1 clustering for signaling, oligomerization of ligand-free and ligand-activated TNFR1 remains controversial. At present, models range from ligand-independent receptor pre-dimerization to ligand-induced oligomerization. Here, we used quantitative, single-molecule superresolution microscopy to study TNFR1 assembly directly in native cellular settings and at physiological cell surface abundance. In the absence of its ligand TNFα, TNFR1 assembled into monomeric and dimeric receptor units. Upon binding of TNFα, TNFR1 clustered predominantly into trimers but also into higher-order oligomers. A functional mutation in the pre-ligand assembly domain (PLAD) of TNFR1 resulted in only monomeric TNFR1, which exhibited impaired ligand binding. In contrast, a form of TNFR1 with a mutation in the ligand-binding CRD2 subdomain retained the monomer-to-dimer ratio of the unliganded wildtype TNFR1 but exhibited no ligand binding. These results underscore the importance of ligand-independent TNFR1 dimerization in NF-ĸB signaling.

Item Type:Article
Refereed:Yes
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:88348
Publisher:AAAS

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