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Now I'll provide a comprehensive review of the GO-CAM model "CARD9 regulation by TRIM62/USP15 (Human)" (gomodel:65d7e4ac00000022).

Review of GO-CAM Model: CARD9 regulation by TRIM62/USP15 (Human)

Model Overview

  • Title: CARD9 regulation by TRIM62/USP15 (Human)
  • Model ID: gomodel:65d7e4ac00000022
  • Taxon: Human (NCBITaxon:9606)
  • Status: Production

Summary of Model Content

This model depicts the regulation of CARD9-mediated signaling through the post-translational modifications by TRIM62 (E3 ubiquitin ligase) and USP15 (deubiquitinase). The pathway represents C-type lectin receptor (CLEC7A/Dectin-1)-mediated antifungal immunity signaling, involving the formation of the CARD9-BCL10-MALT1 (CBM) complex leading to NF-κB activation.

Detailed Evaluation

Biological Accuracy

  1. Pathway Description:
  2. The model accurately represents the known biology of C-type lectin receptor signaling, where CLEC7A (Dectin-1) acts as a pattern recognition receptor for fungal beta-glucans, leading to activation of CARD9 and formation of the CBM complex.

  3. The key regulatory mechanisms involving TRIM62-mediated ubiquitination (activating) and USP15-mediated deubiquitination (inhibitory) of CARD9 are correctly represented.

  4. Protein Functions:

  5. CLEC7A/Dectin-1 (Q9BXN2): Correctly annotated as having pattern recognition receptor activity (GO:0038187) on the plasma membrane, consistent with its role in detecting fungal cell wall components.
  6. CARD9 (Q9H257): Appropriately annotated with signaling adaptor activity (GO:0035591), which aligns with its function as a scaffold protein in immune signaling.
  7. BCL10 (O95999): Correctly annotated with protein-macromolecule adaptor activity (GO:0030674), reflecting its role in the CBM complex.
  8. TRIM62 (Q9BVG3): Properly annotated with ubiquitin protein ligase activity (GO:0061630), consistent with its function in K27-linked ubiquitination of CARD9.

  9. USP15 (Q9Y4E8): Correctly annotated with cysteine-type deubiquitinase activity (GO:0004843), accurately reflecting its role in removing ubiquitin from CARD9.

  10. Cellular Locations:

  11. All proteins are annotated with appropriate cellular locations consistent with their biological functions.
  12. CLEC7A is correctly located at the plasma membrane (GO:0005886).
  13. The cytoplasmic location (GO:0005737) for CARD9, TRIM62, USP15, and BCL10 is consistent with current knowledge.

Modeling Accuracy

  1. Causal Relationships:

  2. The causal relationships in the model are biologically accurate:

    • CLEC7A → CARD9: "directly positively regulates" (RO:0002629)
    • CARD9 → BCL10: "directly positively regulates" (RO:0002629)
    • TRIM62 → CARD9: "directly positively regulates" (RO:0002629)
    • USP15 → CARD9: "directly negatively regulates" (RO:0002630)
    • BCL10 → MALT1: "provides input for" (RO:0002413)

  3. Complex Representation:

  4. The CBM complex formation is represented according to GO-CAM best practices. The model shows how individual components (CARD9, BCL10, MALT1) interact rather than using a generic complex ID, which is appropriate when the specific activities of each component are known.

  5. The sequential activation (CARD9 → BCL10 → MALT1) correctly represents the nucleation model of CBM complex assembly.

  6. Evidence:

  7. All activities and associations are supported by appropriate evidence codes and literature references.
  8. Primary research articles are cited for each relationship (e.g., PMID:26488816 for TRIM62's ubiquitination of CARD9).

Quality Control Issues

  1. Evidence Code Usage:

  2. The evidence for CARD9's part_of relationship to positive regulation of NF-kappaB signaling (GO:0043123) uses ECO:0000250 with evidence from mouse (UniProtKB:Q6QLQ4). While this is acceptable, direct human evidence would strengthen this annotation.

  3. Causal Relationship Precision:

  4. CARD9 is shown to directly positively regulate BCL10, which is accurate but could be more precisely characterized as facilitating the oligomerization of BCL10 through its CARD domain.

  5. Completeness of Model:

  6. The model accurately depicts the key regulatory events but misses some details of CARD9 activation. For instance, the model doesn't explicitly show that CARD9 must be phosphorylated by PKCδ in addition to being ubiquitinated for full activation.

  7. The K27-linked ubiquitination specificity of TRIM62 could be more explicitly noted in the model.

  8. Biological Process Annotation:

  9. BCL10 is annotated as part of "positive regulation of canonical NF-kappaB signal transduction" (GO:0043123), which is accurate, but could also be annotated as part of antifungal immune response for completeness.

Recommendations for Improvement

  1. Activation Mechanism Refinement:

  2. Consider adding a node for PKCδ-mediated phosphorylation of CARD9, which works in conjunction with TRIM62-mediated ubiquitination for full activation.

  3. Ubiquitination Specificity:

  4. Explicitly indicate that TRIM62 mediates K27-linked ubiquitination of CARD9 at K125, which is a specific regulatory mechanism documented in the literature.

  5. Downstream Effects:

  6. The model could be extended to show downstream effects of CBM complex formation, such as activation of NF-κB and production of pro-inflammatory cytokines.

  7. Signaling Context:

  8. Consider adding additional context about how this pathway integrates with other immune signaling pathways, particularly its role in antifungal immunity.

Conclusion

Overall, this GO-CAM model accurately represents the key molecular interactions involved in CARD9 regulation by TRIM62 and USP15 in the context of antifungal immunity signaling. The model adheres to GO-CAM best practices for representing complexes and causal relationships. The biological content is consistent with current literature and follows a logical flow that represents the known activation sequence in this pathway. With minor refinements, this model could serve as an excellent reference for understanding the regulation of CARD9-mediated immune signaling in humans.