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62b4ffe300000241 Poxvirus CRMB inhibition of TNF signaling pathway Human Poxvirus

Let me review the GO-CAM model gomodel:62b4ffe300000241 "Poxvirus-CRMB inhibition of TNF signaling pathway (Human-Poxvirus)."

Model Overview

This model represents the interaction between poxvirus CRMB protein and the human TNF signaling pathway, specifically showing how a viral protein interferes with normal host immune signaling. The model includes:

  1. Human proteins:
  2. TNF (P01375): Cytokine
  3. TNFRSF1A/TNFR1 (P19438): TNF receptor
  4. TRADD (Q15628): Adapter protein
  5. FADD (Q13158): Death domain adapter

  6. TRAF2 (Q12933): TNF receptor-associated factor

  7. Viral protein:

  8. CRMB (P0DSV7): Cytokine response-modifying protein from Variola virus

Biological Accuracy Review

The model represents a well-documented viral immune evasion strategy where poxviruses produce TNF receptor mimics to bind and sequester host TNF, preventing it from activating cellular TNF receptors and downstream signaling pathways.

The UniProt entry for CRMB confirms its function: "Inhibits host immune defense by binding to host TNF and various chemokines in the extracellular space." This is correctly depicted in the model with CRMB (P0DSV7) having "tumor necrosis factor receptor activity" (GO:0005031) and negatively regulating TNF's activity.

The human TNF signaling pathway is accurately depicted with: - TNF (P01375) having cytokine activity (GO:0005125) - TNFRSF1A/TNFR1 (P19438) having TNF receptor activity (GO:0005031) - Adapter proteins (TRADD, FADD, TRAF2) having protein-macromolecule adaptor activity (GO:0030674)

Evaluation of Model Structure and Causal Connections

Examining the causal flow in the model:

  1. TNF positively regulates TNFR1 (using RO:0002629 "directly positively regulates")
  2. TNFR1 positively regulates TRADD (using RO:0002629)
  3. TRADD positively regulates both FADD and TRAF2 (using RO:0002629)
  4. CRMB negatively regulates TNF (using RO:0002630 "directly negatively regulates")

This causal flow correctly represents how: - TNF activates its receptor TNFR1 - TNFR1 recruits the adapter protein TRADD - TRADD recruits additional adapters FADD and TRAF2, which mediate distinct downstream pathways - CRMB acts as a decoy receptor to sequester TNF, preventing its binding to cellular receptors

Cellular Locations

The model shows appropriate cellular locations: - TNF and CRMB are correctly localized in the extracellular space (GO:0005615) - TNFR1 is correctly localized to the plasma membrane (GO:0005886) - Adapter proteins (TRADD, FADD, TRAF2) are properly located at the cytoplasmic side of the plasma membrane (GO:0009898)

Biological Processes

Each protein is appropriately associated with relevant biological processes: - TNF: antiviral innate immune response (GO:0140374) - TNFR1 and TRADD: TNF signaling pathway (GO:0033209) - FADD: apoptotic signaling pathway (GO:0097190) - TRAF2: non-canonical NF-kappaB signaling (GO:0038061)

Assessment of GO-CAM Best Practices

I reviewed the model against best practices for GO-CAM modeling:

  1. Adaptor Proteins: TRADD, FADD, and TRAF2 are correctly annotated as adaptors according to the "How to annotate molecular adaptors" guidelines, with:
  2. Molecular function: protein-macromolecule adaptor activity (GO:0030674)
  3. Appropriate causal relation: "directly positively regulates" to downstream activities

  4. Proper cellular component: cytoplasmic side of plasma membrane

  5. Signaling Receptors: The TNF-TNFR1 relationship follows the "Signaling receptor activity annotation guidelines" for protein ligand-activated signaling receptors:

  6. TNF has ligand activity (cytokine activity GO:0005125)
  7. TNFR1 has receptor activity (GO:0005031)
  8. The causal relation is "directly positively regulates"

  9. Both are in appropriate cellular locations (extracellular space for ligand, plasma membrane for receptor)

  10. Negative Regulation: The viral CRMB protein correctly uses "directly negatively regulates" to indicate its inhibitory effect on TNF activity.

Minor Issues and Recommendations

While the model is generally well-constructed, I note a few points for consideration:

  1. Evidence Codes:
  2. Some causal associations lack specific evidence codes (e.g., the TRADD to TRAF2 relationship has one citation but another has none)

  3. Recommend adding evidence codes for all causal relationships

  4. Additional Information:

  5. The model currently focuses on the initial steps of TNF signaling and its inhibition
  6. The model could potentially be expanded to include more downstream effects, such as NF-κB activation and apoptosis execution

Conclusion

Overall, this GO-CAM model (gomodel:62b4ffe300000241) accurately represents the biological mechanism of how poxvirus CRMB inhibits the TNF signaling pathway. The model:

  1. Correctly depicts protein activities and their locations
  2. Accurately represents the causal flow of TNF signaling
  3. Properly shows how the viral protein CRMB interferes with this pathway
  4. Follows GO-CAM best practices for modeling signaling receptors and adapter proteins

The model provides a clear and parsimonious representation of this viral immune evasion strategy and is consistent with current knowledge about TNF signaling and viral interference mechanisms.