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Based on all the information gathered, I'll now review the GO-CAM model with ID 62b4ffe300003248:

GO-CAM Model Review: Poxvirus-OPG029 inhibition of host HDAC4_STAT2 (Human-Poxvirus)

Model ID: gomodel:62b4ffe300003248
Title: Poxvirus-OPG029 inhibition of host HDAC4_STAT2 (Human-Poxvirus)
Taxon: NCBITaxon:9606 (Human)
Status: Production

Overview

This GO-CAM model describes the interaction between a poxvirus protein (OPG029/C6) and human host proteins (HDAC4 and STAT2) in the context of interferon signaling pathway suppression. The model focuses on how the viral protein C6 inhibits the type I interferon-mediated signaling pathway.

Model Components

The model consists of four main activities:

  1. JAK1 (UniProtKB:P23458) with protein tyrosine kinase activity (GO:0004713)
  2. HDAC4 (UniProtKB:P56524) with molecular adaptor activity (GO:0060090)
  3. STAT2 (UniProtKB:P52630) with DNA-binding transcription factor activity (GO:0003700)
  4. Poxvirus OPG029/C6 (UniProtKB:P17362) with protein sequestering activity (GO:0140311)

Biological Context and Pathway Flow

The model shows that: - JAK1 tyrosine kinase activity directly positively regulates STAT2 transcription factor activity - HDAC4 adaptor activity directly positively regulates STAT2 transcription factor activity - Poxvirus OPG029/C6 protein sequestering activity directly negatively regulates both STAT2 and HDAC4 activities

All activities are part of the type I interferon-mediated signaling pathway (GO:0060337), with the viral protein's activity being part of the viral process "symbiont-mediated suppression of host type I interferon-mediated signaling pathway" (GO:0039502).

Scientific Accuracy Assessment

This model accurately represents the role of poxvirus protein C6 as an inhibitor of type I interferon signaling, which is well supported by the literature reviewed (particularly PMID:27907166). The model correctly shows that:

  1. C6 can interfere with both HDAC4 and STAT2 function
  2. C6 acts late in the IFN signaling pathway, targeting STAT2 transcriptional activity
  3. C6 localizes to both cytoplasm and nucleus, with its viral inhibitory effect occurring in the nucleus

The literature shows that C6 interacts with the transactivation domain of STAT2, providing a mechanism for how it inhibits STAT2-dependent gene transcription, which is consistent with the "protein sequestering activity" (GO:0140311) assigned to C6 in this model.

GO-CAM Compliance Assessment

The model follows GO-CAM guidelines for representing biological pathways:

  1. Molecular functions: Each protein is assigned appropriate molecular functions based on evidence
  2. Causal relationships: The model uses appropriate causal relations (RO:0002629 "directly positively regulates" and RO:0002630 "directly negatively regulates")
  3. Cellular context: All activities have appropriate cellular locations:
  4. JAK1 activity in cytoplasm (GO:0005737)
  5. HDAC4 activity in chromatin (GO:0000785)
  6. STAT2 activity in chromatin (GO:0000785)
  7. Viral protein C6 activity in nucleus (GO:0005634)
  8. Biological process context: All activities are properly placed in their biological processes

Areas for Improvement

  1. JAK1-STAT2 interaction: The model simplifies the JAK-STAT pathway by showing JAK1 directly positively regulating STAT2. In reality, JAK1 phosphorylates STAT2, leading to formation of the ISGF3 complex with STAT1 and IRF9. The model could potentially include STAT1 and IRF9 to more completely represent the pathway.

  2. Evidence for HDAC4-STAT2 interaction: The model shows HDAC4 directly positively regulating STAT2, but the literature examined doesn't clearly establish this direct connection. This aspect might need additional evidence or clarification.

  3. Complex formation: Consider whether the ISGF3 complex (STAT1-STAT2-IRF9) should be explicitly modeled following the guidance in "How to annotate complexes in GO-CAM." Since this is a well-characterized complex where the activities of the individual components are known, it might be more accurate to include all the components.

Suggestions for Improvement

  1. Include STAT1 and IRF9: Expand the model to include STAT1 and IRF9, which together with STAT2 form the ISGF3 complex that binds to ISREs in the promoters of interferon-stimulated genes.

  2. Refine HDAC4 role: Clarify the precise role of HDAC4 in this pathway with additional evidence, or reconsider its inclusion if the interaction is not sufficiently established.

  3. Add additional IFN pathway components: Consider including upstream components (IFNAR receptors) and downstream targets (ISGs) to provide a more complete picture of the type I IFN signaling pathway and how it's disrupted by the viral protein.

  4. Clarify cellular compartments: While the model does include cellular locations, the dynamic translocation of STAT proteins from cytoplasm to nucleus upon activation could be better represented.

Conclusion

This GO-CAM model provides a good representation of how poxvirus protein C6 interferes with type I interferon signaling by targeting STAT2 and HDAC4. The model is scientifically sound and complies with GO-CAM guidelines. With some refinements to better represent the complexities of the JAK-STAT pathway and the inclusion of additional components, this model would provide an even more accurate representation of the biological phenomena it aims to capture.