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Now I'll review the GO-CAM model (gomodel:62b4ffe300000504) based on the available information.

GO-CAM Model Review: Poxvirus-OPG065 inhibition of ZBP1-mediated necroptosis (Human-Poxvirus)

Overview of the Model

This GO-CAM model (gomodel:62b4ffe300000504) depicts the molecular interactions involved in how Vaccinia virus protein OPG065 (E3L) inhibits the ZBP1-mediated necroptosis pathway in human cells. The model represents a host-pathogen interaction where a viral protein interferes with a host defense mechanism.

Proteins in the Model

  1. ZBP1/DAI (UniProtKB:Q9H171) - Z-DNA-binding protein 1 (human)
  2. Function: RNA binding (GO:0003723)
  3. Location: Cytoplasm (GO:0005737)

  4. Process: Antiviral innate immune response (GO:0140374)

  5. OPG065/E3L (UniProtKB:P21605) - RNA-binding protein from Vaccinia virus

  6. Function: RNA binding (GO:0003723)
  7. Location: Cytoplasm (GO:0005737)

  8. Process: Evasion of host immune response (GO:0042783)

  9. RIPK3 (UniProtKB:Q9Y572) - Receptor-interacting serine/threonine-protein kinase 3 (human)

  10. Function: Protein serine/threonine kinase activity (GO:0004674)
  11. Location: Nucleus (GO:0005634)

  12. Process: Necroptotic signaling pathway (GO:0097527)

  13. MLKL (UniProtKB:Q8NB16) - Mixed lineage kinase domain-like protein (human)

  14. Function: Protein serine/threonine kinase activity (GO:0004674)
  15. Location: Plasma membrane (GO:0005886)
  16. Process: Execution phase of necroptosis (GO:0097528)

Pathway and Causal Relationships

The model represents the following pathway:

  1. The viral protein OPG065/E3L (P21605) with RNA binding activity directly negatively regulates (RO:0002630) ZBP1's (Q9H171) RNA binding activity.

  2. ZBP1's RNA binding activity directly positively regulates (RO:0002629) RIPK3's (Q9Y572) protein serine/threonine kinase activity.

  3. RIPK3's protein serine/threonine kinase activity causally upstream positively affects (RO:0002304) MLKL's (Q8NB16) protein serine/threonine kinase activity.

Scientific Correctness Assessment

The model correctly represents the ZBP1-RIPK3-MLKL necroptosis pathway based on current scientific understanding:

  1. Mechanistic correctness: The model accurately shows that ZBP1 acts as a sensor that, upon activation, recruits and activates RIPK3, which then phosphorylates MLKL to execute necroptosis.

  2. Viral inhibition: The model correctly depicts how the viral protein E3L inhibits this pathway by competing with ZBP1 for binding to Z-form RNA, preventing ZBP1 activation.

  3. Cellular localization: The locations specified for each protein are consistent with their known subcellular distributions. RIPK3 is shown to be in the nucleus during viral infection (which is accurate for influenza virus infection), and MLKL is correctly shown at the plasma membrane where it executes the final step of necroptosis.

  4. Causal relationships: The causal relationships (directly negatively regulates, directly positively regulates, and causally upstream of with positive effect) appropriately model the mechanisms described in the literature.

Suggested Improvements

  1. Evidence Sources: The model uses relevant PMIDs for evidence, though we couldn't retrieve the full text of PMID:34192517. This appears to be the key paper describing E3L's role in preventing Z-RNA sensing by ZBP1.

  2. Mechanistic Detail: The model could be enhanced by specifically mentioning Z-RNA as the molecule that ZBP1 senses during viral infection. This could be done by adding a transport or localization of Z-RNA component.

  3. Additional Components: Consider including the trimerization of MLKL after phosphorylation by RIPK3, which is a critical step in the execution of necroptosis.

  4. Temporal Aspect: The model doesn't explicitly represent the temporal sequence of events during infection, though this is implied by the causal relationships.

Compliance with GO-CAM Practices

The model follows GO-CAM best practices:

  1. Proper use of causal relations: The model uses appropriate causal relation predicates (RO:0002630, RO:0002629, RO:0002304) to connect activities.

  2. Cellular context: Each activity is appropriately contextualized within a cellular component.

  3. Biological process context: Each activity is properly associated with a biological process term.

  4. Evidence and provenance: Each assertion has evidence codes and references to the scientific literature.

Comments on Automated Changes

The model shows two automated changes: - "RO:0002212 replaced by RO:0002630" (negatively regulates → directly negatively regulates) - "RO:0002213 replaced by RO:0002629" (positively regulates → directly positively regulates)

These changes are appropriate as they provide more specific relationship types that better reflect the direct nature of the regulations in the model.

Conclusion

This GO-CAM model provides a clear and scientifically accurate representation of how Vaccinia virus protein E3L inhibits ZBP1-mediated necroptosis. The model effectively captures the key molecular interactions and causal relationships in this host-pathogen interaction. It meets GO-CAM standards for biological accuracy, proper use of ontology terms, and evidence-based assertions.

The model is parsimonious and focused on the core pathway, making it easy to understand while still capturing the essential biological mechanisms involved in this viral evasion of host defense.