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62b4ffe300000906 Poxvirus OPG065 inhibition of ISG15 conjugation Human Poxvirus

Now that I have gathered all the relevant information about the model and its components, let me review the GO-CAM model "gomodel:62b4ffe300000906" titled "Poxvirus-OPG065 inhibition of ISG15 conjugation (Human-Poxvirus)".

GO-CAM Model Review: Poxvirus-OPG065 inhibition of ISG15 conjugation (Human-Poxvirus)

Model Summary

This GO-CAM model (https://bioregistry.io/go.model:62b4ffe300000906) represents a host-pathogen interaction between human ISG15 (Interferon-Stimulated Gene 15) conjugation system and the poxvirus protein OPG065 (also known as E3 protein). The model describes how the viral protein OPG065 inhibits the ISG15 conjugation pathway through protein sequestering activity, which is part of the viral mechanism to evade host innate immune responses.

Activities and Entities in the Model

The model includes 5 key activities:

  1. ISG15 protein tag activity (GO:0031386)
  2. Enabled by: ISG15 (UniProtKB:P05161)
  3. Part of: ISG15-protein conjugation (GO:0032020)

  4. Occurs in: cytoplasm (GO:0005737)

  5. Protein sequestering activity (GO:0140311)

  6. Enabled by: Vaccinia virus OPG065/E3 protein (UniProtKB:P21605)
  7. Part of: symbiont-mediated suppression of host ISG15-protein conjugation (GO:0039579)
  8. Occurs in: cytoplasm (GO:0005737)

  9. Directly negatively regulates ISG15 protein tag activity

  10. ISG15 transferase activity (GO:0042296)

  11. Enabled by: HERC5 (UniProtKB:Q9UII4)
  12. Part of: ISG15-protein conjugation (GO:0032020)
  13. Occurs in: cytoplasm (GO:0005737)

  14. Directly positively regulates ISG15 protein tag activity

  15. ISG15 transferase activity (GO:0042296)

  16. Enabled by: UBE2L6 (UniProtKB:O14933)
  17. Part of: ISG15-protein conjugation (GO:0032020)
  18. Occurs in: cytoplasm (GO:0005737)

  19. Directly positively regulates HERC5 ISG15 transferase activity

  20. ISG15 activating enzyme activity (GO:0019782)

  21. Enabled by: UBA7 (UniProtKB:P41226)
  22. Part of: ISG15-protein conjugation (GO:0032020)
  23. Occurs in: cytoplasm (GO:0005737)
  24. Directly positively regulates UBE2L6 ISG15 transferase activity

Evaluation of the Model

Strengths:

  1. Scientific Accuracy: The model correctly represents the ISG15 conjugation pathway, which involves UBA7 (E1 enzyme), UBE2L6 (E2 enzyme), and HERC5 (E3 enzyme) in the conjugation of ISG15 to target proteins. This matches the published literature (PMID:16407192, PMID:15131269).

  2. Causal Relationships: The causal relationships between the activities are logically connected and follow the correct enzymatic cascade:

  3. UBA7 activates ISG15 and regulates UBE2L6
  4. UBE2L6 transfers ISG15 and regulates HERC5
  5. HERC5 conjugates ISG15 to target proteins

  6. The poxvirus OPG065/E3 protein inhibits ISG15 protein tag activity

  7. Cellular Context: All activities are correctly annotated as occurring in the cytoplasm, which is consistent with the known subcellular localization of these proteins.

  8. Host-Pathogen Interaction: The model effectively captures the host-pathogen interaction, showing how the viral protein interferes with the host immune response.

Areas for Improvement:

  1. Missing Target Information: The model doesn't specify which protein(s) the poxvirus OPG065/E3 actually sequesters. Based on the literature (PMID:24257616), OPG065/E3 counteracts ISG15 by binding to it directly, but this specific interaction is not fully represented.

  2. Biological Process Annotation: While the viral protein's activity is correctly annotated as being part of "symbiont-mediated suppression of host ISG15-protein conjugation" (GO:0039579), it might be helpful to also connect this to the broader biological process of viral evasion of host immune response.

  3. Evidence Documentation: While the model includes evidence codes and references to PMIDs, adding more specific evidence for the viral protein's sequestering activity would strengthen the model.

  4. Incomplete Representation of ISG15 Targets: The model doesn't include the various cellular proteins that are targets of ISG15 conjugation. Including at least some key targets would provide a more complete picture of the pathway.

Compliance with GO-CAM Best Practices

  1. Protein Sequestering Activity Representation: According to the "Protein sequestering activity" guidelines, the relation between the protein that acts to sequester and its target should be "has input." This relationship is missing in the current model - the OPG065/E3 protein should have ISG15 as its input.

  2. Causal Relationships: The model correctly uses "directly negatively regulates" for the inhibitory relationship between the viral protein and ISG15 activity, which is appropriate for a direct protein-protein interaction.

  3. Enzymatic Cascade Representation: The model correctly represents the enzymatic cascade with appropriate predicates (directly positively regulates) between the E1, E2, and E3 enzymes.

Recommendations for Improvement

  1. Add Direct Input Relationship: Add a "has input" relationship from the OPG065 protein sequestering activity to ISG15 to clarify that the viral protein directly interacts with and sequesters ISG15.

  2. Add Additional Context: Consider adding broader biological processes such as "innate immune response" or "antiviral defense" to provide context for the ISG15 conjugation pathway.

  3. Include ISG15 Targets: Consider expanding the model to include at least one representative target of ISG15 conjugation to show the downstream effects of ISG15 modification.

  4. Add Specific Evidence: Include more specific evidence statements for the sequestering activity of the OPG065/E3 protein.

Conclusion

This GO-CAM model effectively represents the inhibition of the human ISG15 conjugation pathway by the poxvirus OPG065/E3 protein. It correctly shows the enzymatic cascade of the ISG15 conjugation system and how the viral protein interferes with this system. With a few minor improvements, particularly the addition of a direct input relationship between the viral protein and ISG15, this model would provide a comprehensive and accurate representation of this host-pathogen interaction.