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Based on all this information, I'll now review the GO-CAM model (gomodel:63c0ac2b00000008) that represents the AIM2 inflammasome pathway.

Review of GO-CAM Model: The AIM2 Inflammasome (Human)

Model ID: gomodel:63c0ac2b00000008

Overview

This model captures the AIM2 inflammasome pathway in humans, which plays a critical role in innate immune responses by detecting cytosolic double-stranded DNA, leading to inflammation and pyroptotic cell death. The model represents the sequential activities and causal relationships between the key proteins involved in this pathway: AIM2, PYCARD/ASC, Caspase-1 (CASP1), and Gasdermin-D (GSDMD).

Components and Pathway Flow

  1. Initiating Event: AIM2 (UniProtKB:O14862) senses cytosolic double-stranded DNA through its:
  2. Double-stranded DNA binding activity (GO:0003690)

  3. Pattern recognition receptor activity (GO:0038187)

  4. Inflammasome Assembly: AIM2 recruits PYCARD/ASC through:

  5. Signaling adaptor activity (GO:0035591)

  6. PYCARD then activates CASP1 through cysteine-type endopeptidase activator activity (GO:0140608)

  7. Caspase Activation: CASP1 (UniProtKB:P29466) becomes active through:

  8. Cysteine-type endopeptidase activity (GO:0004197)

  9. Leads to protein maturation processes (GO:0051604)

  10. Effector Functions: GSDMD (UniProtKB:P57764) mediates:

  11. Phosphatidylinositol-4,5-bisphosphate binding (GO:0005546)
  12. Wide pore channel activity (GO:0022829)
  13. Positive regulation of inflammatory response (GO:0050729)

Strengths of the Model

  1. Comprehensive Pathway Coverage: The model captures the entire sequence from DNA sensing to inflammasome formation, caspase activation, and pyroptosis induction.

  2. Appropriate Causal Relationships: The model correctly uses RO:0002629 (directly positively regulates) to indicate the direct activation relationships between the pathway components.

  3. Subcellular Localization: Appropriate subcellular locations are included for each activity (e.g., cytoplasm for AIM2, plasma membrane for GSDMD).

  4. Evidence Quality: Each assertion is supported by high-quality experimental evidence (ECO:0000314 - direct assay evidence used in manual assertion) with appropriate literature citations.

Areas for Improvement

  1. Missing Potential Intermediates: The model does not capture potential intermediate steps between GSDMD binding phosphatidylinositol-4,5-bisphosphate and its pore-forming activity. Recent research indicates that GSDMD undergoes palmitoylation at Cys-191 (as shown in UniProtKB:P57764), which is essential for its membrane targeting and pore formation.

  2. Cleavage Events Not Explicitly Modeled: The proteolytic cleavage of GSDMD by CASP1 at Asp-275 to release the N-terminal fragment is implied but not explicitly captured. This is a critical event for pyroptosis induction.

  3. Missing Final Outcomes: While the model shows GSDMD pore formation, it doesn't explicitly capture downstream consequences such as IL-1β/IL-18 release or cell lysis through NINJ1 activation.

  4. Complex Formation Representation: The AIM2 inflammasome complex assembly (GO:0140970) is indicated as part of the process, but the model does not explicitly show the oligomerization of these components into the inflammasome speck, which is a key structural feature of this pathway.

Consistency with GO-CAM Best Practices

  1. Causal Association Predicates: The model appropriately uses RO:0002629 (directly positively regulates) throughout to indicate direct positive regulation between sequential steps.

  2. Molecular Function Representation: Each activity is correctly represented as a molecular function enabled by the appropriate gene product.

  3. Process Association: Each activity is appropriately located within the relevant biological process, such as AIM2 inflammasome complex assembly (GO:0140970) or positive regulation of inflammatory response (GO:0050729).

  4. Evidence and Provenance: Each assertion is properly supported with evidence codes, literature references, and contribution statements.

Suggested Improvements

  1. Add GSDMD Cleavage: Explicitly model the CASP1-mediated cleavage of GSDMD at Asp-275, releasing the N-terminal domain that forms pores.

  2. Include GSDMD Palmitoylation: Recent research (UniProtKB:P57764, references 37-39) shows that palmitoylation at Cys-191 is critical for GSDMD function. This post-translational modification could be included.

  3. Capture Downstream Consequences: Expand the model to include the release of pro-inflammatory cytokines (IL-1β, IL-18) through the GSDMD pores and subsequent events leading to pyroptotic cell death.

  4. Represent Inflammasome Speck Formation: AIM2 and PYCARD form distinct filamentous structures in the inflammasome speck, which could be explicitly represented.

  5. Include Potential Regulatory Mechanisms: Consider including negative regulatory mechanisms such as succination of GSDMD at cysteine residues, which can inactivate GSDMD and block pyroptosis (UniProtKB:P57764, reference 24).

Conclusion

This GO-CAM model provides a solid foundation for representing the AIM2 inflammasome pathway. It correctly captures the key molecular activities and causal relationships in the pathway, from DNA sensing to pore formation. The model adheres to GO-CAM best practices regarding evidence standards and relationship types.

To further enhance its biological completeness, the model could be expanded to include recent discoveries about protein modifications, complex formation details, and downstream consequences of inflammasome activation. These additions would provide a more comprehensive representation of this important innate immune pathway.