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Based on all the information gathered, I'll now provide a review of GO-CAM model gomodel:5f46c3b700001407, titled "TBK1 activation via TRAF3 autoubiquitination (Human)".

Review of GO-CAM Model: TBK1 activation via TRAF3 autoubiquitination (Human)

Model ID: gomodel:5f46c3b700001407

Overview

This model represents the signaling pathway leading to TBK1 activation through TRAF3 autoubiquitination in human cells. It focuses on positive regulation of type I interferon production (GO:0032481), which is a critical process in innate immune responses to viral and bacterial infections.

Model Structure

The model consists of 7 activities connected through causal relationships:

  1. TICAM2 (UniProtKB:Q86XR7) - Molecular adaptor activity (GO:0060090) occurring in endosome (GO:0005768)
  2. TICAM1 (UniProtKB:Q8IUC6) - Molecular adaptor activity (GO:0060090) occurring in endosome (GO:0005768)
  3. TRAF3 (UniProtKB:Q13114) - Ubiquitin protein ligase activity (GO:0061630) occurring in endosome (GO:0005768)
  4. MAVS (UniProtKB:Q7Z434) - Molecular adaptor activity (GO:0060090) occurring in mitochondrion (GO:0005739)
  5. TRAF3IP3 (UniProtKB:Q9Y228) - Molecular adaptor activity (GO:0060090) occurring in mitochondrion (GO:0005739)
  6. TRAF3 (UniProtKB:Q13114) - Ubiquitin protein ligase activity (GO:0061630) occurring in mitochondrion (GO:0005739)
  7. TBK1 (UniProtKB:Q9UHD2) - Protein serine/threonine kinase activity (GO:0004674) occurring in cytoplasm (GO:0005737)

Causal Flow Analysis

The causal flow in this model follows two main pathways:

  1. Endosomal pathway: TICAM2 → TICAM1 → TRAF3 (endosomal) → TBK1
  2. Mitochondrial pathway: MAVS → TRAF3IP3 → TRAF3 (mitochondrial) → TBK1

Both pathways converge on TBK1 activation, which leads to type I interferon production. The causal connections use RO:0002629 (directly positively regulates), indicating direct positive regulation.

Scientific Accuracy Assessment

Based on the published literature provided (PMID:19898473 and PMID:14703513), the model appears scientifically accurate. The papers describe:

  1. TRAF3's critical role in type I interferon responses
  2. The importance of TRAF3 ubiquitination in regulating IFN production
  3. TBK1's function as a protein serine/threonine kinase that phosphorylates IRF3
  4. The involvement of adaptor proteins like TICAM1/TICAM2 (also known as TRIF/TRAM) in engaging TRAF3
  5. MAVS as a mitochondrial adaptor for TRAF3 in virus-induced signaling

Adherence to GO-CAM Best Practices

Overall, the model follows GO-CAM best practices:

  1. Molecular adaptor annotation: The model correctly represents molecular adaptor activities (GO:0060090) for TICAM1, TICAM2, MAVS, and TRAF3IP3. According to guidelines, these adaptors should use "directly positively regulates" (RO:0002629) relations to downstream activities, which is correctly implemented.

  2. E3 ubiquitin ligase representation: TRAF3 is appropriately annotated with ubiquitin protein ligase activity (GO:0061630). The guidelines indicate E3 ligases should be connected to downstream processes they regulate.

  3. Cellular component annotation: Each activity is correctly annotated with its cellular location (endosome, mitochondrion, or cytoplasm).

  4. Biological process annotation: All activities are properly connected to their biological process, "positive regulation of type I interferon production" (GO:0032481).

  5. Evidence annotation: Each activity is supported by experimental evidence (ECO:0000314 - direct assay evidence) with appropriate PMID references.

Suggestions for Improvement

  1. Add inputs to molecular adaptors: According to the guidelines, molecular adaptors should have inputs specified (the molecules they bring together). The current model doesn't specify inputs for any of the adaptor proteins.

  2. Clarify TRAF3 autoubiquitination: The title mentions TRAF3 autoubiquitination, but this is not explicitly modeled. The model could more clearly show that TRAF3 ubiquitin ligase activity is self-directed, perhaps by adding TRAF3 as an input to its own activity.

  3. Include IRF3 activation: Given that TBK1 ultimately phosphorylates and activates IRF3 leading to IFN production (as shown in PMID:14703513), the model could be extended to include this final step in the pathway.

  4. Distinguish K63 vs K48 ubiquitination: The paper (PMID:19898473) discusses distinct modes of TRAF3 ubiquitination (K63-linked for the IFN pathway vs. K48-linked for degradation). This distinction could be made clearer in the model.

Conclusion

GO-CAM model gomodel:5f46c3b700001407 accurately represents the signaling pathway for TBK1 activation via TRAF3 autoubiquitination. It correctly implements GO-CAM best practices for molecular adaptor and E3 ligase annotation. The model effectively captures two distinct pathways (endosomal and mitochondrial) leading to TBK1 activation in type I interferon production. With minor enhancements to specify inputs for adaptors and more explicitly model TRAF3 autoubiquitination, this would be an exemplary representation of this signaling pathway.