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Now let me put together a comprehensive review of GO-CAM model 63d320cd00000225.

Review of GO-CAM Model: Activation of the AIM2 inflammasome in response to DNA damage (Mouse)

Model Information

  • ID: gomodel:63d320cd00000225
  • Title: Activation of the AIM2 inflammasome in response to DNA damage (Mouse)
  • Taxon: Human (NCBITaxon:9606) - Note: There appears to be an inconsistency here as the title refers to mouse but the taxon is human.
  • Status: Production

Model Summary

This GO-CAM model describes the activation pathway of the AIM2 inflammasome in response to DNA damage. The model depicts a series of molecular functions and causal relationships centered on how AIM2 (Absent in melanoma 2) acts as a cytosolic DNA sensor that triggers the assembly of the inflammasome, eventually leading to pyroptotic inflammatory response.

The model includes the following key components: 1. AIM2 (MGI:MGI:2686159) detection of DNA damage 2. Caspase-1 (MGI:MGI:96544) activation 3. GSDMD (Gasdermin D, MGI:MGI:1916396) pore formation 4. Inflammatory response induction

Detailed Review

Scientific Content Assessment

The model accurately represents the current scientific understanding of AIM2 inflammasome activation as supported by the literature. Key findings from references such as PMID:27846608 and PMID:27383986 align with the model structure:

  1. AIM2 serves as a cytoplasmic DNA sensor that detects double-stranded DNA damage at sites of double-strand breaks.
  2. Upon DNA binding, AIM2 activates the inflammasome through a signaling adaptor activity.
  3. This leads to activation of caspase-1, which cleaves pro-IL-1β and GSDMD.
  4. Cleaved GSDMD forms pores in the plasma membrane, resulting in pyroptotic cell death.

The causal flow of activities in the model correctly represents the biological pathway as described in the literature.

Technical Structure Assessment

The model demonstrates a coherent structure with appropriate causal relationships between activities:

  1. DNA Binding and Recognition:
  2. AIM2 "double-stranded DNA binding" (GO:0003690) occurs in the "site of double-strand break" (GO:0035861)

  3. AIM2 "pattern recognition receptor activity" (GO:0038187) is correctly shown as directly positively regulating the next step

  4. Inflammasome Activation:

  5. AIM2 "signaling adaptor activity" (GO:0035591) is present, consistent with its known role

  6. AIM2's "cysteine-type endopeptidase activator activity" (GO:0140608) correctly shows it activates caspase-1

  7. Caspase-1 Activation:

  8. Caspase-1 "cysteine-type endopeptidase activity" (GO:0004197) is shown as part of "protein maturation" (GO:0051604)

  9. Caspase-1 is shown activating GSDMD, which is consistent with the literature

  10. GSDMD Pore Formation:

  11. GSDMD "phosphatidylinositol-4,5-bisphosphate binding" (GO:0005546) occurs at the "plasma membrane" (GO:0005886)
  12. GSDMD "wide pore channel activity" (GO:0022829) is shown as part of "positive regulation of inflammatory response" (GO:0050729)

GO-CAM Best Practices Assessment

The model generally adheres to GO-CAM best practices:

  1. Use of correct causal relations: The model uses "RO:0002629" (directly positively regulates) appropriately to connect sequential activities in the pathway.

  2. Molecular function assignments: Each protein has been assigned appropriate molecular functions based on experimental evidence.

  3. Cellular component annotations: Activities are correctly localized to appropriate cellular components (e.g., AIM2 DNA binding at sites of double-strand breaks, GSDMD pore formation at the plasma membrane).

  4. Biological process annotations: Each activity is associated with appropriate biological processes.

  5. Evidence codes: The model uses ECO:0000314 (direct assay evidence used in manual assertion) and ECO:0000250 (sequence similarity evidence used in manual assertion) appropriately.

Areas for Improvement

While the model is generally well-constructed, there are a few areas that could be improved:

  1. Taxon inconsistency: The title refers to mouse ("Mouse"), but the taxon is listed as human (NCBITaxon:9606). This should be corrected for consistency.

  2. Pycard/ASC representation: The model mentions "MGI:MGI:1931465" (Pycard/ASC) in the objects list but does not include it in the pathway. Since ASC is a crucial adaptor for the AIM2 inflammasome, it would be beneficial to explicitly show its role in connecting AIM2 to caspase-1.

  3. IL-1β processing: While the model shows the activation of the inflammasome machinery, it could be enhanced by including the processing and release of IL-1β, which is a major functional outcome of inflammasome activation.

  4. Complex formation: According to the GO-CAM best practices for annotating complexes, the AIM2 inflammasome complex could be more explicitly modeled. Since the model focuses on the AIM2 inflammasome, it would be beneficial to either explicitly show the complex formation or follow the guidelines for representing complexes in GO-CAM.

Conclusion

The GO-CAM model "Activation of the AIM2 inflammasome in response to DNA damage" (gomodel:63d320cd00000225) is a well-constructed representation of the AIM2 inflammasome pathway. It accurately captures the scientific understanding of how DNA damage activates the AIM2 inflammasome, leading to caspase-1 activation, GSDMD pore formation, and subsequent inflammatory response.

The model follows GO-CAM best practices for most aspects, with appropriate molecular functions, cellular components, biological processes, and causal relationships. The evidence provided is appropriate and linked to relevant literature.

To further enhance this model, I recommend: 1. Resolving the taxon inconsistency (mouse vs. human) 2. Explicitly including ASC/Pycard in the pathway 3. Adding the processing and release of IL-1β 4. Considering a more explicit representation of the AIM2 inflammasome complex according to GO-CAM best practices for complex annotation

Overall, this is a valuable model that effectively captures current knowledge about the AIM2 inflammasome activation pathway in response to DNA damage.