Tumor Necrosis Factor Receptor Mechanisms in Cellular Responses

Tumor necrosis factor (TNF) exerts its diverse effects on cell fate and function through two principal receptors, TNFR1 (p55) and TNFR2 (p75). Binding of the TNF trimer to TNFR1 recruits adaptor proteins via a cytosolic death domain, assembling complexes that direct either apoptotic caspase cascades or activate pro-survival transcription factors such as NF-κB and AP-1. TNFR2, lacking a death domain, modulates immune cell survival and proliferation through TRAF-dependent pathways and may enhance TNFR1 signalling by concentrating ligand at the cell surface. The balance between receptor internalisation, ectodomain shedding and de novo synthesis governs the magnitude and duration of TNF responses. Heterocomplex formation between p55 and p75 receptors further refines downstream outcomes by altering affinity, signal strength and cellular localisation. Dysregulation of these receptor mechanisms underlies chronic inflammation, autoimmunity and tumour progression, while selective modulation of TNFR1 or TNFR2 offers therapeutic potential in conditions ranging from rheumatoid arthritis to cancer. Advances in structural biology and engineered ligand variants promise receptor-biased agents that can tilt the response towards tissue protection or immune activation as required.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Tumor Necrosis Factor Receptor Mechanisms in Cellular Responses publication trend

The graph below shows the total number of articles in tumor necrosis factor receptor mechanisms in cellular responses across all publications each year (not limited to Nature Index journals).

Technical terms

TNFα trimer: Three TNFα monomers assembled into the active ligand form.

TNFR1 (p55): TNF receptor containing a death domain that can trigger apoptosis or NF-κB activation.

TNFR2 (p75): TNF receptor lacking a death domain, signalling mainly through TRAF adaptors to promote cell survival.

Ligand passing: Mechanism by which one receptor subtype captures and transfers ligand to another to modulate signal strength.

Ectodomain shedding: Proteolytic release of the receptor’s extracellular portion, regulating receptor availability on the cell surface.

References

1. Особенности изменений уровня экспрессии рецепторов TNFFα и функционального ответа клеточных линий при стимуляции различными дозами цитокина. Medical Immunology (Russia) (2023).
2. The Structure of Tumor Necrosis Factor-α at 2.6 Å Resolution Implications for receptor binding. Journal of Biological Chemistry (1989).
3. Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor.. Journal of Biological Chemistry (1993).
4. Ligand-induced Formation of p55 and p75 Tumor Necrosis Factor Receptor Heterocomplexes on Intact Cells*. Journal of Biological Chemistry (1997).
5. Structural requirements for inducible shedding of the p55 tumor necrosis factor receptor.. Journal of Biological Chemistry (1994).
6. Continuous internalization of tumor necrosis factor receptors in a human myosarcoma cell line.. Journal of Biological Chemistry (1988).