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Based on my review, I'll now provide a detailed assessment of the GO-CAM model gomodel:65288b2200001166 titled "TRIM55 and TRIM21-mediated inhibition of NFKB2 (Human)".

GO-CAM Review: TRIM55 and TRIM21-mediated inhibition of NFKB2 (Human)

Model Overview

This model (gomodel:65288b2200001166) represents the molecular mechanisms by which TRIM55 and TRIM21 regulate the non-canonical NF-κB signaling pathway through ubiquitination of NFKB2 (p100/p52) in human cells. The model captures how TRIM55 facilitates TRIM21-mediated K63-linked ubiquitination of VCP, which in turn promotes K48-linked ubiquitin-dependent degradation of NFKB2, ultimately inhibiting its DNA-binding transcription activator activity.

Model Structure and Accuracy

The model includes five key activities:

  1. TRIM55's E3 ubiquitin ligase activity (GO:0061630) targeting VCP for K48-linked ubiquitination
  2. TRIM55's protein-macromolecule adaptor activity (GO:0030674)
  3. TRIM21's E3 ubiquitin ligase activity (GO:0061630) mediating K63-linked ubiquitination
  4. VCP's K48-linked polyubiquitin modification-dependent protein binding activity (GO:0036435)
  5. NFKB2's DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228)

Correct aspects:

  1. Proper evidence and citations: The model uses appropriate evidence codes and citations, with most activities citing PMID:37816088 using ECO:0000314 (direct assay evidence).

  2. Appropriate causal relationships: The causal relationships between activities use the proper relation types:

  3. TRIM55's adaptor activity provides input for (RO:0002413) TRIM21's ligase activity
  4. TRIM55's ligase activity provides input for (RO:0002413) VCP's binding activity
  5. TRIM21's ligase activity directly positively regulates (RO:0002629) VCP's binding activity

  6. VCP's binding activity directly negatively regulates (RO:0002630) NFKB2's transcription activity

  7. Appropriate biological process annotations: Each activity is associated with relevant biological processes:

  8. TRIM55's ubiquitin ligase activity is part of protein K48-linked ubiquitination (GO:0070936)
  9. TRIM55's adaptor activity is part of positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224)
  10. TRIM21's ligase activity is part of protein K63-linked ubiquitination (GO:0070534)
  11. VCP's binding activity is part of positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224)

  12. NFKB2's activity is part of canonical NF-kappaB signal transduction (GO:0007249)

  13. Correct subcellular locations: Activities are appropriately localized:

  14. TRIM55 and TRIM21 are in the cytoplasm (GO:0005737)
  15. NFKB2 is in the nucleus (GO:0005634)
  16. VCP is in the cytoplasm (GO:0005737)

Discrepancies and Suggested Improvements

  1. Clarification of NF-κB pathway: The model associates NFKB2's transcription activity with canonical NF-κB signaling (GO:0007249), but according to the PMID:37816088 paper, TRIM55 specifically regulates the non-canonical NF-κB pathway. This association should be updated to non-canonical NF-kappaB signaling.

  2. VCP's role clarification: While the model accurately represents VCP's activity based on the cited publication, it could be clearer about the specific mechanism by which VCP promotes NFKB2 processing. According to the paper, VCP, upon K63-linked ubiquitination by TRIM21, helps in extracting and processing p100 (NFKB2) to generate p52.

  3. Missing molecular details: The model doesn't explicitly capture the formation of the VCP-UFD1-NPL4 complex, which according to the paper is crucial for p100 processing. Considering adding this complex or noting its role.

  4. Incomplete representation of the pathway: The model focuses on the inhibitory aspect of NFKB2 regulation, but doesn't fully capture that this processing is actually part of the activation of the non-canonical NF-κB pathway (as p52 generation is a necessary step).

  5. Biological process associations: While the current biological process associations are generally appropriate, consider adding more specific terms related to B-cell immune responses or germinal center formation, which are highlighted as downstream consequences in the paper.

Compliance with GO-CAM Best Practices

Based on the GO-CAM guidelines for E3 ubiquitin ligases:

  1. E3 ligase activity annotation: The model correctly represents TRIM55 and TRIM21 with ubiquitin protein ligase activity (GO:0061630) and appropriate biological processes describing the type of ubiquitination (K48-linked and K63-linked, respectively).

  2. Complex annotation: The model correctly represents the individual activities rather than using a complex term, which is appropriate since the specific activities of each protein are known.

  3. Causal relationships: The model properly uses the "provides input for" and "directly regulates" (positively or negatively) relationships between activities as specified in the guidelines.

Conclusion

Overall, this is a well-constructed GO-CAM model that accurately represents the molecular mechanisms described in the primary literature. It follows most GO-CAM best practices for representing E3 ubiquitin ligases and their regulatory networks. The few suggested improvements would make the model even more precisely aligned with the biological mechanisms described in the source paper.

The model could be enhanced by: 1. Correcting the pathway association for NFKB2 from canonical to non-canonical NF-κB signaling 2. Possibly adding the VCP-UFD1-NPL4 complex formation 3. Clarifying the dual role of p100 processing as both inhibition of full-length NFKB2 and activation of p52-mediated signaling 4. Adding more specific downstream biological processes related to B-cell function

Despite these minor suggestions, the model is generally accurate, well-evidenced, and properly represents the molecular mechanisms described in the literature.