Skip to content

Based on my review of the GO-CAM model and literature, I'll now provide a comprehensive review and QC evaluation.

Review of GO-CAM Model 63c0ac2b00000088: The AIM2 inflammasome (Mouse)

Summary

This GO-CAM model (ID: gomodel:63c0ac2b00000088) represents the AIM2 inflammasome pathway in mouse. The model depicts how the AIM2 sensor recognizes cytosolic double-stranded DNA, which leads to the activation of a signaling cascade resulting in pyroptotic inflammatory cell death.

Pathway Overview

The model correctly captures the sequential activation steps of the AIM2 inflammasome:

  1. AIM2 (MGI:MGI:2686159) acts as a pattern recognition receptor, binding to cytosolic double-stranded DNA (GO:0003690)
  2. Upon activation, AIM2 recruits the adaptor protein ASC/PYCARD
  3. This complex activates Caspase-1 (Casp1, MGI:MGI:96544)
  4. Caspase-1 cleaves Gasdermin-D (Gsdmd, MGI:MGI:1916396), which translocates to the plasma membrane
  5. Gasdermin-D forms pores in the membrane (GO:0022829), leading to cell death through pyroptosis and release of inflammatory mediators

Strengths of the Model

  1. The model correctly represents the key molecular functions of the AIM2 inflammasome components:
  2. AIM2's double-stranded DNA binding (GO:0003690)
  3. AIM2's pattern recognition receptor activity (GO:0038187)
  4. AIM2's signaling adaptor activity (GO:0035591)
  5. Caspase-1's cysteine-type endopeptidase activity (GO:0004197)
  6. Gasdermin-D's phosphatidylinositol-4,5-bisphosphate binding (GO:0005546)

  7. Gasdermin-D's wide pore channel activity (GO:0022829)

  8. The cellular locations are accurately represented:

  9. AIM2 functions in the cytoplasm (GO:0005737)

  10. Gasdermin-D acts at the plasma membrane (GO:0005886)

  11. The model correctly uses causal connections (RO:0002629 "directly positively regulates") to represent the signaling cascade, showing how each protein's activity positively regulates the next step.

  12. The biological processes are appropriately annotated:

  13. AIM2 inflammasome complex assembly (GO:0140970)
  14. Protein maturation (GO:0051604)

  15. Positive regulation of inflammatory response (GO:0050729)

  16. Evidence codes and literature references are appropriately cited throughout the model.

Potential Areas for Improvement

  1. Complex Representation: According to GO-CAM guidelines on complex annotation, the AIM2 inflammasome itself could be better represented. The model correctly shows individual proteins and their activities, but it doesn't explicitly represent the formation of the AIM2-ASC-caspase-1 complex. While this is implied through the causal relationships, it might be beneficial to explicitly represent the complex using a GO term for the AIM2 inflammasome complex (GO:0097169).

  2. Missing Intermediate Steps: The model doesn't explicitly show the ASC/PYCARD protein, which is a critical adapter between AIM2 and caspase-1. While the activity flow is correct, the omission of this component might make the model less complete.

  3. IL-1β Release: The end result of AIM2 inflammasome activation includes the release of mature IL-1β and IL-18, which is not represented in this model. Although the model correctly focuses on the pyroptotic pathway through Gasdermin-D, the parallel inflammatory cytokine release pathway is an important part of inflammasome biology.

  4. Feedback Mechanisms: The model doesn't include any regulatory or feedback mechanisms that might control inflammasome activation. Recent literature shows that AIM2 inflammasome activity is tightly regulated to prevent inappropriate activation.

Literature Consistency

The model is well supported by the literature, including key references: - PMID:19158679 describing AIM2 as a cytoplasmic DNA sensor for the inflammasome - PMID:32109412 documenting caspase-1's role in pyroptosis - PMID:27383986 explaining Gasdermin-D's role in forming membrane pores

These references correctly support the molecular functions and biological processes represented in the model.

Technical QC

  1. Predicate Usage: The model appropriately uses RO:0002629 "directly positively regulates" for causal relationships between activities, which is consistent with GO-CAM guidelines.

  2. Evidence: Each assertion is backed by appropriate evidence codes (primarily ECO:0000314 "direct assay evidence used in manual assertion" and ECO:0000250 "sequence similarity evidence used in manual assertion").

  3. Annotations: All GO term annotations appear to be correctly applied to the appropriate proteins and activities.

Conclusion and Recommendations

This is a high-quality GO-CAM model that accurately represents the AIM2 inflammasome pathway leading to pyroptosis. The model is well-supported by scientific literature and follows GO-CAM annotation guidelines.

Recommendations for enhancement: 1. Consider explicitly representing the ASC/PYCARD adapter protein to complete the canonical inflammasome complex. 2. Consider adding the parallel pathway leading to IL-1β maturation and release. 3. Add the AIM2 inflammasome complex term (GO:0097169) to better represent the complex formation. 4. Potentially include some of the known regulatory mechanisms that control AIM2 inflammasome activation.

Overall, this model provides a clear and accurate representation of the AIM2 inflammasome pathway leading to pyroptosis, making it a valuable resource for understanding this important innate immune mechanism.