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Let me now review the GO-CAM model based on all the information I've gathered. I'll need to check if it follows the GO-CAM best practices and if the biological representation is accurate.

GO-CAM Review: gomodel:639bc18f00000090

Model Overview

Title: Isg12a K6-ubiquitination by TRIM21 leading to pyroptosis (Human)

Taxon: Human (NCBITaxon:9606)

Status: Production

This model represents a pathway showing how TRIM21 (an E3 ubiquitin ligase) regulates virus-induced cell pyroptosis through polyubiquitination of ISG12a/IFI27 (an interferon-stimulated gene), leading to caspase-3 activation and eventually gasdermin E (GSDME)-mediated pyroptosis.

Pathway Analysis

The model describes four main activities in the following causal pathway:

  1. TRIM21 (P19474) - Ubiquitin protein ligase activity (GO:0061630)
  2. Located in cytoplasm (GO:0005737)
  3. Part of protein K6-linked ubiquitination process (GO:0085020)

  4. Directly positively regulates ISG12a/IFI27

  5. ISG12a/IFI27 (P40305) - Molecular adaptor activity (GO:0060090)

  6. Located in mitochondrion (GO:0005739)
  7. Part of pyroptotic inflammatory response (GO:0070269)

  8. Causally upstream of, positive effect on Caspase-3

  9. Caspase-3 (P42574) - Cysteine-type endopeptidase activity (GO:0004197)

  10. Located in cytoplasm (GO:0005737)
  11. Part of pyroptotic inflammatory response (GO:0070269)

  12. Directly positively regulates Gasdermin E

  13. Gasdermin E (O60443) - Wide pore channel activity (GO:0022829)

  14. Located in plasma membrane (GO:0005886)
  15. Part of pyroptotic inflammatory response (GO:0070269)
  16. Terminal step in the pathway

Model Accuracy Review

After examining the literature and molecular function data, I find the GO-CAM model is well-constructed and accurately represents the current scientific understanding of this pathway:

  1. Evidence Base: The model is well-supported by primary literature (PMID:36426955), which specifically describes the role of TRIM21 in regulating virus-induced cell pyroptosis through IFI27 (ISG12a) ubiquitination.

  2. Molecular Functions: The molecular functions assigned to each protein are accurate:

  3. TRIM21 is correctly annotated as an E3 ubiquitin ligase that catalyzes K6-linked ubiquitination of ISG12a
  4. ISG12a/IFI27 is correctly shown with molecular adaptor activity, as it functions to recruit caspase-3 to the mitochondria
  5. Caspase-3 is correctly identified as the protease that cleaves Gasdermin E

  6. Gasdermin E is correctly shown with its pore-forming activity

  7. Subcellular Locations: The subcellular locations are accurately represented:

  8. TRIM21 in cytoplasm
  9. ISG12a/IFI27 in mitochondrion
  10. Caspase-3 in cytoplasm

  11. Gasdermin E in plasma membrane

  12. Causal Relationships: The causal associations between activities follow the biological process accurately, with appropriate relationship predicates:

  13. TRIM21 directly positively regulates (RO:0002629) ISG12a
  14. ISG12a causally upstream of, positive effect (RO:0002304) on Caspase-3
  15. Caspase-3 directly positively regulates (RO:0002629) Gasdermin E

Compliance with GO-CAM Best Practices

The model follows GO-CAM best practices:

  1. Molecular activities are properly assigned to specific gene products
  2. Causal relationships between activities use appropriate predicates
  3. Cellular locations are properly annotated for each activity
  4. Biological processes are properly assigned to activities
  5. Evidence is provided for each assertion with appropriate ECO codes and literature references

Biological Accuracy

The biological pathway represented in this model is consistent with current understanding:

  1. TRIM21-mediated ISG12a ubiquitination: The literature (PMID:36426955) confirms that TRIM21 mediates K6-linked polyubiquitination of ISG12a at Lys-69, which facilitates its translocation to mitochondria.

  2. ISG12a's role in caspase-3 activation: The research confirms that ISG12a, after ubiquitination and mitochondrial translocation, causes caspase-3 activation.

  3. Caspase-3 cleavage of Gasdermin E: Literature (PMID:28459430) confirms that caspase-3 cleaves Gasdermin E at Asp-270, releasing its N-terminal domain.

  4. Gasdermin E pore formation: The cleaved Gasdermin E N-terminal domain has been confirmed to form pores in the plasma membrane, leading to pyroptosis.

Conclusion

The GO-CAM model gomodel:639bc18f00000090 is a high-quality representation of the TRIM21-ISG12a-Caspase3-GSDME pathway leading to pyroptosis. It accurately reflects the scientific literature, correctly applies molecular function terms, and properly represents the causal relationships between activities.

Key strengths of this model: - Accurate molecular function annotations - Correct subcellular localization - Appropriate causal relationships - Strong evidence base with relevant literature citations

No significant issues or inaccuracies were identified in this model. It provides a clear and accurate representation of the biological pathway by which TRIM21-mediated ubiquitination of ISG12a leads to pyroptosis through caspase-3 activation and Gasdermin E pore formation.