Summary: TNFR1 receptors organize into ordered clusters on the cell surface, joining trimers into higher-order oligomers that drive pro-inflammatory signaling linked to many diseases.
Source: University of Reading
New research reveals that inflammation is regulated by a distinct, highly organized arrangement of receptors that move and assemble across the cell surface.
The findings, published in Science Signaling, shed light on how cells interpret inflammatory cues and decide whether to die, divide, or migrate. The international team, led by researchers at the University of Reading with collaborators in Frankfurt and Würzburg, used state-of-the-art imaging to observe how the tumor necrosis factor receptor 1 (TNFR1) arranges itself into defined structures that control signaling outcomes.
The group describes how TNFR1 receptors form triangular assemblies by linking together in a coordinated way—likened by the researchers to dancers joining arms—which changes how cells respond to inflammatory signals.
Dr Darius Widera, Associate Professor at the University of Reading, commented:
“This discovery significantly advances our understanding of cell signaling and could guide future drug development. The precise pattern of receptor ‘dance’ on the cell surface influences whether inflammatory signals trigger cell death, proliferation, or migration—processes relevant to both immune function and cancer.”
“Inflammation is governed by a lock-and-key mechanism in which signaling molecules engage specific surface proteins. By revealing the structural arrangements of the receptors that mediate these inflammatory responses, we now have a clearer picture of how cells control these critical decisions.”
“Chronic inflammation contributes to many major diseases, including cancer and Alzheimer’s disease. Understanding how triangular clusters of TNFR1 shape cellular responses may enable new therapies that reduce harmful inflammation while avoiding some side effects of current treatments.”
The researchers directly visualized, for the first time in living cells at physiological receptor levels, how TNFR1 molecules assemble into highly ordered oligomers. Using quantitative single-molecule super-resolution microscopy, they tracked receptor organization before and after activation by its ligand, TNFα.
In the absence of ligand, the team observed TNFR1 primarily as monomers and dimers on the cell membrane. After TNFα binding, receptors shifted majorly into trimeric units and assembled further into higher-order oligomers. These larger assemblies are associated with the activation of pro-inflammatory pathways that influence NF-κB signaling, cell survival, proliferation, and programmed cell death.
The study also examined the effects of specific receptor mutations. A mutation in the receptor’s preligand assembly domain produced receptors that remained monomeric and showed impaired ligand binding, demonstrating the functional importance of preligand dimerization. Another mutation in the ligand-binding domain prevented ligand binding without altering the monomer–dimer balance of the unliganded receptor, highlighting distinct structural contributions to receptor function.
Dr Sjoerd van Wijk of the Institute for Experimental Tumor Research in Pediatrics and the Frankfurt Foundation for Children with Cancer said:
“TNF must be activated before it can engage a membrane receptor—so it behaves like a key that fits the lock only under specific conditions. This precision helps protect healthy cells from unwanted death. Despite TNFα’s medical importance, how its receptors behave on the membrane was not well understood. Our results, showing both ligand-independent dimerization and ligand-driven oligomerization, are relevant to cancer and excessive inflammatory reactions such as rheumatoid arthritis, and they suggest new paths for therapeutic control.”
Source:
University of Reading
Media contacts:
Press Office – University of Reading
Image source:
The image is in the public domain.
Original research:
“Single-molecule imaging reveals the oligomeric state of functional TNFα-induced plasma membrane TNFR1 clusters in cells”, Christos Karathanasis et al., Science Signaling. DOI: 10.1126/scisignal.aax5647 (closed access).
Abstract
Single-molecule imaging reveals the oligomeric state of functional TNFα-induced plasma membrane TNFR1 clusters in cells
Activation of tumor necrosis factor receptor 1 (TNFR1) by its ligand TNFα controls NF-κB signaling, cell proliferation, programmed cell death, and cellular survival, and is centrally involved in inflammation, autoimmune diseases, and cancer progression. Although TNFR1 clustering is known to influence signaling, the receptor’s oligomeric states—both without ligand and after ligand binding—have been debated. Using quantitative single-molecule super-resolution microscopy in native cellular contexts at physiological receptor densities, the authors show that unliganded TNFR1 exists mainly as monomers and dimers, while TNFα binding promotes trimer formation and further assembly into higher-order oligomers. Functional disruption of the receptor’s preligand assembly domain produced monomers with reduced ligand binding, whereas a ligand-binding domain mutation abolished TNFα binding without altering the monomer–dimer ratio of the unliganded receptor. These observations emphasize the role of ligand-independent TNFR1 dimerization in downstream NF-κB signaling and highlight structural mechanisms that may be targeted to modulate inflammatory responses.