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Based on the model details and the literature I've reviewed, I'll now provide a comprehensive review of GO-CAM model 662af8fa00002225 "Gsdmd palmitoylation by Zdhhc5 and Zdhhc9 promotes pyroptosis (Mouse)".

Review of GO-CAM Model: gomodel:662af8fa00002225

Summary

This model captures the molecular pathway of GSDMD (Gasdermin D) palmitoylation by ZDHHC5 and ZDHHC9, which promotes pyroptosis in mouse. The model describes how caspase-4 cleaves GSDMD, allowing GSDMD to form pores in the plasma membrane, leading to pyroptotic cell death.

Structure and Content Assessment

Strengths:

  1. Evidence and References: The model is well-supported with appropriate references (PMIDs: 30135078, 38530158, 27339137, etc.) and evidence codes (ECO:0000314, ECO:0000250, ECO:0000315).

  2. Causal Associations: The causal relationships between activities are logically established, showing a clear pathway from palmitoylation to pyroptosis.

  3. Cellular Compartments: Each activity has appropriate cellular compartment specifications (plasma membrane, cytosol, etc.).

  4. Process Associations: Each activity is placed in its correct biological process context.

Areas for Improvement:

  1. Tax𐅍on Inconsistency: The model title specifies "Mouse" but the taxon field is set to "NCBITaxon:9606" (human). This should be corrected to "NCBITaxon:10090" (mouse) to match the model content, as all the proteins are mouse proteins (MGI IDs).

  2. Causal Association Evidence: Some causal associations lack explicit evidence codes and references, particularly:

  3. The causal association between GSDMD's phosphatidylinositol-4,5-bisphosphate binding (662af8fa00002245) and wide pore channel activity (662af8fa00002249)

  4. The causal association between Casp4's activity (662af8fa00002231) and GSDMD's binding activity (662af8fa00002245)

  5. Incomplete Predicate Use: While the model correctly uses RO:0002629 (directly positively regulates) and RO:0002304 (causally upstream of, positive effect), it also uses RO:0002407 which appears to be potentially incorrect or outdated. The intended relationship was likely one of the standard causal predicates.

  6. Pathway Completeness: Based on PMID:38530158, ROS also facilitates the palmitoylation process, but this is not captured in the model. Consider adding this aspect for completeness.

Biological Content Assessment

  1. Mechanism Accuracy: The model correctly captures that ZDHHC5 and ZDHHC9 are palmitoylating GSDMD at Cys191/Cys192, which is supported by the reference (PMID:38530158).

  2. Cleavage Process: According to PMID:30135078, Caspase-4 (Casp4) cleaves GSDMD at Asp276, which is an essential step for pyroptosis. While the cleavage activity is represented, the specific cleavage site could be more explicitly captured.

  3. Pore Formation Mechanism: The sequence of events from phosphatidylinositol-4,5-bisphosphate binding to wide pore channel formation is accurately represented, aligning with the literature (PMID:27339137).

  4. NLRP3 Connection: The model includes NLRP3's signaling adaptor activity, which is connected to the pathway. This is consistent with the role of NLRP3 in pyroptosis as described in the literature.

Recommendations

  1. Fix Taxon: Change the taxon from human (NCBITaxon:9606) to mouse (NCBITaxon:10090) to match the model content.

  2. Add Evidence to Causal Associations: Provide evidence codes and references for all causal associations.

  3. Review Predicates: Ensure all relationship predicates are correctly applied, especially checking RO:0002407.

  4. Consider Adding ROS Facilitation: The paper mentioned that reactive oxygen species (ROS) facilitate the palmitoylation process - this could be added to the model for completeness.

  5. Add Specificity to Cleavage Site: Consider adding information about the specific cleavage site (Asp276) in GSDMD, which is critical for its activation.

  6. Consider Adding FASN: PMID:38530158 mentions Fatty Acid Synthase (FASN) as a GSDMD-binding partner. Consider adding this interaction to the model if it provides important context.

Conclusion

Overall, this is a well-constructed GO-CAM model that effectively captures the molecular pathway of GSDMD palmitoylation by ZDHHC5 and ZDHHC9 leading to pyroptosis. With the suggested improvements, particularly fixing the taxon inconsistency and adding evidence to all causal associations, the model will more accurately represent the biological process and align better with GO-CAM best practices.