TNFR2 (TNFRSF1B Protein)

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TNFR2 (TNFRSF1B Protein)

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TNFR2 (TNFRSF1B Protein)

Introduction

TNFR2 (TNF Receptor 2, p75, CD120b; encoded by the [TNFRSF1B gene](/genes/tnfrsf1b)) 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.

Overview

TNFR2 is a type I transmembrane glycoprotein of 461 amino acids that belongs to the TNF receptor superfamily[1]. Unlike [TNFR1](/genes/tnfrsf1a), 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](/cell-types/oligodendrocytes) protection, and anti-inflammatory microglial polarization[3]. [@faustman2010]

<div class="infobox infobox-protein"> [@probert2015]

| | | [@mccoy2018]
|---|---| [@fischer2018]
| Protein Name | TNF Receptor 2 (TNFR2, p75, CD120b) |
| Gene | [TNFRSF1B](/genes/tnfrsf1b) |
| UniProt ID | [P20333](https://www.uniprot.org/uniprot/P20333) |
| Molecular Weight | ~75 kDa (glycosylated) |
| Length | 461 amino acids |
| Subcellular Localization | Plasma membrane (type I transmembrane) |
| Function | TNF receptor; cell survival, neuroprotection |

</div>

Structure

Domain Organization

TNFR2 has a modular extracellular-transmembrane-intracellular architecture[1]:

...

TNFR2 (TNFRSF1B Protein)

Introduction

TNFR2 (TNF Receptor 2, p75, CD120b; encoded by the [TNFRSF1B gene](/genes/tnfrsf1b)) 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.

Overview

TNFR2 is a type I transmembrane glycoprotein of 461 amino acids that belongs to the TNF receptor superfamily[1]. Unlike [TNFR1](/genes/tnfrsf1a), 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](/cell-types/oligodendrocytes) protection, and anti-inflammatory microglial polarization[3]. [@faustman2010]

<div class="infobox infobox-protein"> [@probert2015]

| | | [@mccoy2018]
|---|---| [@fischer2018]
| Protein Name | TNF Receptor 2 (TNFR2, p75, CD120b) |
| Gene | [TNFRSF1B](/genes/tnfrsf1b) |
| UniProt ID | [P20333](https://www.uniprot.org/uniprot/P20333) |
| Molecular Weight | ~75 kDa (glycosylated) |
| Length | 461 amino acids |
| Subcellular Localization | Plasma membrane (type I transmembrane) |
| Function | TNF receptor; cell survival, neuroprotection |

</div>

Structure

Domain Organization

TNFR2 has a modular extracellular-transmembrane-intracellular architecture[1]:

Extracellular domain: Four cysteine-rich domains (CRD1-4) that form the TNF-binding interface
CRD1: Pre-ligand assembly domain (PLAD) mediating receptor trimerization
CRD2-3: Primary TNF contact surfaces
Transmembrane domain: Single-pass α-helix
Intracellular domain: ~235 aa signaling domain; recruits TRAF1/2/3 via a TRAF-binding motif (SKEE)

Key Structural Difference from TNFR1

TNFR2 critically lacks a death domain (DD), which is present in TNFR1[2]. This structural distinction underlies their divergent signaling:

TNFR1: DD → TRADD → FADD → Caspase-8 → [Apoptosis](/entities/apoptosis)
TNFR2: No DD → TRAF2/TRAF3 → [NF-κB](/entities/nf-kb) → Survival genes

Ligand Specificity

TNFR2 preferentially binds transmembrane TNF (tmTNF) over soluble TNF[3]:

tmTNF is the 26 kDa membrane-anchored form, before TACE/ADAM17 cleavage
This selectivity means TNFR2 is primarily activated through cell-cell contact
Soluble TNF activates TNFR1 more efficiently than TNFR2

Signaling Pathways

Pro-Survival Signaling

TNFR2 activates several survival cascades[2]:

Non-canonical NF-κB: TRAF2/3 degradation → NIK stabilization → IKKα → p52/RelB nuclear translocation → anti-apoptotic gene expression (Bcl-xL, cIAP1/2)

PI3K/Akt: Activates [Akt](/proteins/akt1-protein) for cell survival and glucose metabolism

MAPK/ERK: Mitogenic signaling through Ras-Raf-MEK-ERK cascade

Canonical NF-κB: Also activates classical NF-κB (p65/p50) for inflammatory gene regulation

Neuroprotective Mechanisms

In the CNS, TNFR2 signaling provides neuroprotection through[3]:

Anti-apoptotic gene induction: Bcl-2, Bcl-xL, Mn-SOD
Neurotrophic factor release: Stimulates [BDNF](/genes/bdnf) and [NGF](/genes/ngf) from glial cells
Antioxidant defense: Upregulates Mn-SOD and glutathione pathways
Synaptic homeostasis: Modulates AMPA receptor trafficking for synaptic scaling
Treg expansion: Promotes immunosuppressive regulatory T cells in the CNS

Role in Neurodegeneration

Protective vs. Destructive TNF Signaling

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 |

Disease-Specific Roles

[Alzheimer's disease](/diseases/alzheimers-disease): TNFR2 promotes microglial [Aβ](/proteins/amyloid-beta) clearance; TNFR2 agonism reduces plaque burden in models
[Parkinson's disease](/diseases/parkinsons-disease): Protects dopaminergic [neurons](/entities/neurons); TNFR2 KO worsens MPTP toxicity
[Multiple sclerosis](/diseases/multiple-sclerosis): Essential for remyelination; explains anti-TNF therapy failure in MS
Stroke: TNFR2 signaling reduces infarct volume and promotes post-ischemic recovery

Protein Interactions

| 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 |

Clinical Significance

Therapeutic Targeting

Selective TNFR2 modulation is a promising therapeutic strategy[5]:

TNFR2 agonist antibodies: Activate protective signaling and Treg expansion
XPro1595: Dominant-negative soluble TNF that blocks TNFR1 while preserving TNFR2 signaling
Engineered TNF muteins: R1antTNF and similar molecules selectively activate TNFR2
Soluble TNFR2 (Etanercept): Decoy receptor that blocks both TNFR1 and TNFR2 — contraindicated in MS

Biomarker Value

Soluble TNFR2 (sTNFR2): Shed from cell surface by TACE/ADAM17; elevated in CSF in AD and correlates with disease progression
CSF sTNFR2: Potential biomarker for neuroinflammatory status

External Links

[TNFR2 - UniProt](https://www.uniprot.org/uniprot/P20333)
[TNFRSF1B - NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/7133)

References

[Wajant H et al., Tumor necrosis factor signaling (2003) (2003)](https://doi.org/10.1038/sj.cdd.4401189)

[Unknown, Faustman D & Davis M, TNF receptor 2 pathway: drug target for autoimmune diseases (2010) (2010)](https://doi.org/10.1038/nrd3030)

[Unknown, Probert L, TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects (2015) (2015)](https://doi.org/10.1016/j.neuroscience.2015.06.038)

[Unknown, McCoy MK & Bhatt DG, TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease (2018) (2018)](https://doi.org/10.1186/s12974-018-1075-3)

[Fischer R et al., Selective activation of tumor necrosis factor receptor II induces anti-inflammatory responses and reduces experimental arthritis (2018) (2018)](https://doi.org/10.1002/art.40413)

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Related Entities

TNFRSF1BPROTEIN

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entity_type	protein
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wiki_page_id	wp-dd6f801be85a
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

TNFR2 (TNFRSF1B Protein)

TNFR2 (TNFRSF1B Protein)

Introduction

Overview

Structure

Domain Organization

TNFR2 (TNFRSF1B Protein)

Introduction

Overview

Structure

Domain Organization

Key Structural Difference from TNFR1

Ligand Specificity

Signaling Pathways

Pro-Survival Signaling

Neuroprotective Mechanisms

Role in Neurodegeneration

Protective vs. Destructive TNF Signaling

Disease-Specific Roles

Protein Interactions

Clinical Significance

Therapeutic Targeting

Biomarker Value

See Also

External Links

References

💬 Discussion