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bioRxiv · 10.1101/2024.08.09.607302

Intra-cluster receptor density (IRD) dictates TNFR1 clusters' signaling efficacy

Jana, S.·Roy, P.·Das, J.·Biswas, P.·Nanda, N.·Sinha, B.·Sinha, D.
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Abstract

Tumor Necrosis Factor Receptor 1 (TNFR1) signaling regulates cell fate in inflammation, immune responses, and tumorigenesis. While TNF--mediated TNFR1 pathways are well known, the role of receptor clustering remains unclear. Utilizing homo-FRET using fluorescence anisotropy, we show that intra-cluster receptor density (IRD) governs TNFR1 signaling outcomes. Soluble TNF- (sTNF-) increases IRD at cluster cores but decreases it at rims via receptor reorganization. Reducing IRD through membrane tension, zafirlukast, actin depolymerization, or cholesterol depletion suppresses sTNF- signaling, whereas increasing IRD by lowering membrane tension or exposing cells in a 3D gel-like microenvironment triggers ligand-independent activation. These findings reveal IRD as a key regulator of receptor signaling, with potential relevance across related receptor families and innovative strategies in modulating TNFR1 signaling. TeaserIntra-cluster receptor density (IRD) is critical for TNFR1 signal modulation, with higher IRD activating and lower IRD impairing the TNFR1 signaling.

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Jana, S., Roy, P., Das, J., Biswas, P., Nanda, N., Sinha, B., Sinha, D.. 2024-08-09. Intra-cluster receptor density (IRD) dictates TNFR1 clusters' signaling efficacy. https://doi.org/10.1101/2024.08.09.607302

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