Skip to content

Now I'll analyze the GO-CAM model in detail based on the information I've gathered.

GO-CAM Model Review: HHV1-US3 inhibition of host RIG-I signaling (Human-Herpesvirus)

Model Overview

Model ID: gomodel:62b4ffe300005697
Title: HHV1-US3 inhibition of host RIG-I signaling (Human-Herpesvirus)
Taxon: Human (NCBITaxon:9606)
Status: Production

Model Components

This GO-CAM model describes how the US3 kinase from Herpes Simplex Virus 1 (HHV-1) inhibits the RIG-I signaling pathway in human cells. The model includes 4 key activities:

  1. US3 Kinase activity (UniProtKB:P04413 - protein serine/threonine kinase activity)
  2. RIG-I Pattern Recognition Receptor activity (UniProtKB:O95786 - pattern recognition receptor activity)
  3. TRIM25 E3 Ubiquitin Ligase activity (UniProtKB:Q14258 - ubiquitin protein ligase activity)
  4. MAVS Signaling Adaptor activity (UniProtKB:Q7Z434 - signaling adaptor activity)

The model illustrates how HSV-1 US3 kinase directly negatively regulates TRIM25's ability to ubiquitinate RIG-I, thereby suppressing the downstream antiviral signaling pathway.

Analysis of Evidence and Scientific Accuracy

The model is based on two primary scientific publications: - PMID:31801859 - Evidence for US3 kinase of HHV1 inhibiting RIG-I signaling - PMID:34935440 - Detailed mechanism showing US3 phosphorylates RIG-I at S8 position

The model correctly represents the causal relationships between these components based on the cited literature:

  1. US3 kinase (P04413) directly negatively regulates TRIM25 (Q14258) activity
  2. TRIM25 (Q14258) directly positively regulates RIG-I (O95786) activity through K63-linked ubiquitination
  3. RIG-I (O95786) directly positively regulates MAVS (Q7Z434) activity

The evidence shows that US3 phosphorylates RIG-I specifically at S8, suppressing TRIM25-mediated RIG-I ubiquitination and subsequent RIG-I-MAVS binding, ultimately inhibiting type I IFN induction.

Conformity with GO-CAM Best Practices

The model follows several GO-CAM best practices:

  1. Proper molecular functions: Each protein is annotated with the correct molecular function:
  2. US3: Protein serine/threonine kinase activity (GO:0004674)
  3. RIG-I: Pattern recognition receptor activity (GO:0038187)
  4. TRIM25: Ubiquitin protein ligase activity (GO:0061630)

  5. MAVS: Signaling adaptor activity (GO:0035591)

  6. Appropriate causal relations: The model uses the correct relation predicates:

  7. RO:0002630 (directly negatively regulates) for US3's effect on TRIM25

  8. RO:0002629 (directly positively regulates) for TRIM25's effect on RIG-I and RIG-I's effect on MAVS

  9. Cellular location: Each activity is properly annotated with subcellular location:

  10. US3: Host cell cytoplasm (GO:0030430)
  11. RIG-I: Cytoplasm (GO:0005737)
  12. TRIM25: Cytoplasm (GO:0005737)

  13. MAVS: Mitochondrial membrane (GO:0031966)

  14. Biological process context: Each activity is appropriately placed in the relevant biological process:

  15. US3: Symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway (GO:0039540)
  16. RIG-I: Cytoplasmic pattern recognition receptor signaling pathway (GO:0002753)
  17. TRIM25: Cytoplasmic pattern recognition receptor signaling pathway (GO:0002753)
  18. MAVS: Cytoplasmic pattern recognition receptor signaling pathway (GO:0002753)

Evidence Quality

The model uses evidence codes correctly: - ECO:0000314 (direct assay evidence used in manual assertion) for experimental evidence - ECO:0000305 (curator inference used in manual assertion) for subcellular localization

The model cites relevant peer-reviewed literature that directly supports the assertions made.

Areas for Improvement

While this is a well-constructed model, I would suggest the following improvements:

  1. Additional Detail: The model could be enhanced by directly capturing US3's phosphorylation of RIG-I at serine-8 (S8), which is a key molecular event detailed in PMID:34935440. This would provide a more precise mechanistic representation.

  2. Expanded Context: The model could benefit from including downstream effects, such as the inhibition of IRF3 activation and type I interferon production, which would provide a more complete picture of the biological significance.

  3. Potential Update to Relationships: The model currently shows US3 directly negatively regulating TRIM25, but PMID:34935440 indicates that US3 directly targets RIG-I by phosphorylating it at S8, which then prevents TRIM25-mediated ubiquitination. The model could more accurately represent this by showing US3 directly negatively regulating RIG-I, which then affects TRIM25's ability to ubiquitinate RIG-I.

Conclusion

This GO-CAM model (gomodel:62b4ffe300005697) is a scientifically accurate representation of how HSV-1 US3 kinase inhibits the RIG-I signaling pathway in human cells. It follows GO-CAM best practices for molecular function annotation, causal relationships, cellular location, and biological process context. The model is properly supported by evidence from relevant peer-reviewed literature.

The minor improvements suggested would enhance the mechanistic precision and biological context of the model, but do not detract from its overall quality and accuracy.