TNFR2 (TNF Receptor 2, p75, CD120b; encoded by the TNFRSF1B gene is a 75 kDa transmembrane receptor for tumor necrosis factor that primarily mediates neuroprotective and cell survival signaling, in contrast to the death-promoting TNFR1.
TNFR2 is a type I transmembrane glycoprotein of 461 amino acids that belongs to the TNF receptor superfamily[1]. Unlike TNFR1, TNFR2 lacks an intracellular death domain and instead signals through TRAF (TNF receptor-associated factor) proteins to promote cell survival, tissue repair, and immunomodulation[2]. In the CNS, TNFR2 is the primary mediator of TNF's neuroprotective effects, including neuronal survival, oligodendrocyte protection, and anti-inflammatory microglial polarization[3]. [1]
| | | [2]
|---|---| [3]
| Protein Name | TNF Receptor 2 (TNFR2, p75, CD120b) |
| Gene | TNFRSF1B |
| UniProt ID | P20333 |
| Molecular Weight | ~75 kDa (glycosylated) |
| Length | 461 amino acids |
| Subcellular Localization | Plasma membrane (type I transmembrane) |
| Function | TNF receptor; cell survival, neuroprotection |
TNFR2 has a modular extracellular-transmembrane-intracellular architecture[1]:
TNFR2 critically lacks a death domain (DD), which is present in TNFR1[2]. This structural distinction underlies their divergent signaling:
TNFR2 preferentially binds transmembrane TNF (tmTNF) over soluble TNF[3]:
TNFR2 activates several survival cascades[2]:
In the CNS, TNFR2 signaling provides neuroprotection through[3]:
The TNFR1/TNFR2 balance determines whether TNF signaling is neurotoxic or neuroprotective[4]:
| Condition | TNFR1 Activity | TNFR2 Activity | Outcome |
|---|---|---|---|
| Healthy CNS | Low | Constitutive | Homeostasis, synaptic plasticity |
| Early neuroinflammation | Elevated | Elevated | Mixed — some protection, some damage |
| Chronic neurodegeneration | High | Reduced | Net neurotoxicity, progressive damage |
| Therapeutic intervention | Blocked (selective) | Preserved/enhanced | Neuroprotection, repair |
| Interactor | Type | Function |
|---|---|---|
| TNF (transmembrane) | Ligand (preferred) | Activates TNFR2 through cell-cell contact |
| TNF (soluble) | Ligand (weak) | Low-affinity binding |
| Lymphotoxin-α (LTα) | Ligand | Alternative ligand for TNFR2 |
| TRAF1 | Adaptor | Recruited to intracellular domain |
| TRAF2 | Adaptor | Key signaling mediator for NF-κB |
| TRAF3 | Adaptor | Non-canonical NF-κB regulation |
| cIAP1/2 | Effector | Ubiquitin ligases in NF-κB signaling |
Selective TNFR2 modulation is a promising therapeutic strategy[5]:
Faustman D & Davis M, TNF receptor 2 pathway: drug target for autoimmune diseases (2010). 2010. ↩︎
McCoy MK & Bhatt DG, TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease (2018). 2018. ↩︎
Fischer R et al. Selective activation of tumor necrosis factor receptor II induces anti-inflammatory responses and reduces experimental arthritis (2018). 2018. ↩︎