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Based on the review of the GO-CAM model and related information, I'll now provide a thorough review of the GO-CAM model "gomodel:613aae0000000813" titled "Liver apoptosis regulation by CASP6 (Human)".

Review of GO-CAM Model: Liver apoptosis regulation by CASP6 (Human)

Model Summary

ID: gomodel:613aae0000000813
Title: Liver apoptosis regulation by CASP6 (Human)
Taxon: Human (NCBITaxon:9606)
Status: Production

Model Overview

This model represents the molecular pathway for CASP6 (Caspase-6) regulation in liver apoptosis, specifically focusing on how the AMP-activated protein kinase (AMPK) inhibits CASP6 activation to prevent excessive hepatocyte death in nonalcoholic steatohepatitis (NASH). The model is based primarily on research by Zhao et al. (2020) published in Science (PMID:32029622).

The model contains four key activities: 1. BID (P55957-4) enabling cysteine-type endopeptidase regulator activity (GO:0043028) 2. PRKAA1 (Q13131-2) enabling protein serine/threonine kinase activity (GO:0004674) 3. PRKAA2 (P54646) enabling protein serine/threonine kinase activity (GO:0004674) 4. CASP6 (P55212) enabling cysteine-type endopeptidase activity (GO:0004197)

Pathway Analysis

The model depicts the following regulatory pathway: - Both PRKAA1 and PRKAA2 (AMPK α1 and α2 subunits) negatively regulate CASP6 through their protein serine/threonine kinase activity - CASP6, when active, positively regulates BID through its cysteine-type endopeptidase activity - BID, when cleaved by CASP6, participates in positive regulation of cytochrome c release from mitochondria

This pathway accurately reflects findings from Zhao et al. (2020), showing that: 1. AMPK phosphorylates CASP6 at Ser-257, preventing its activation 2. When AMPK activity is reduced (as in NASH), CASP6 becomes activated 3. Active CASP6 cleaves BID to induce cytochrome c release 4. This creates a feedforward loop that leads to hepatocyte death

Evidence Assessment

The model is well-supported by evidence: - The relationship between CASP6 and BID is supported by experimental evidence from PMID:15661737 and PMID:32029622 - The regulatory relationships between AMPK (PRKAA1/PRKAA2) and CASP6 are supported by experimental evidence from PMID:32029622 - The biological processes (hepatocyte apoptotic process, release of cytochrome c) are well-supported by experimental evidence

The evidence types used (ECO:0000314 - direct assay evidence, ECO:0000304 - author statement supported by traceable reference) are appropriate for the assertions made.

Compliance with GO-CAM Guidelines

The model follows GO-CAM best practices: - Appropriate use of causal relationships (RO:0002630 "directly negatively regulates" and RO:0002629 "directly positively regulates") - Correct representation of protein activities and biological processes - Proper association of activities with biological processes

Consistency with Current Knowledge

The model is consistent with current understanding of AMPK-CASP6 regulation in liver damage. Zhao et al. (2020) demonstrated that: 1. AMPK phosphorylates CASP6 at Ser-257, preventing its activation 2. In NASH, reduced AMPK activity leads to increased CASP6 activation 3. CASP6 cleaves BID at specific sites (Asp59 and Asp75) 4. Cleaved BID induces cytochrome c release from mitochondria

The model accurately captures this mechanism.

Recent Changes and Annotations

The model includes an automated change from 2024-10-10 where GO:0097153 was replaced by GO:0004197 (cysteine-type endopeptidase activity), reflecting ongoing ontology maintenance.

Recommendations for Improvement

While the model is generally well-constructed, I suggest the following improvements:

  1. Add molecular details of phosphorylation: The model could be enhanced by specifically indicating that AMPK phosphorylates CASP6 at Ser-257. This detail is crucial for understanding the mechanism and is well-supported by the Zhao et al. paper.

  2. Include the feedback loop: The model shows CASP6 cleaving BID, but doesn't fully capture the feedforward loop described in the paper where cleaved BID induces cytochrome c release, which further activates upstream caspases. This feedback mechanism is an important aspect of how CASP6 sustains apoptosis in hepatocytes.

  3. Add additional molecular players: The model could include other components mentioned in the paper, such as:

  4. Executioner caspases (CASP3 and CASP7) that initially cleave CASP6

  5. Cytochrome c and its role in activating the caspase cascade

  6. Clarify BID cleavage sites: The model could specify the cleavage sites on BID (Asp59 and Asp75) as these are specifically identified in the paper.

  7. Update GO term for BID: BID's activity is currently annotated as "cysteine-type endopeptidase regulator activity involved in apoptotic process" (GO:0043028), but based on the paper, it might be more appropriate to use "BH3 domain binding" or "pro-apoptotic activity" as BID acts as a BH3-only protein that promotes apoptosis after being cleaved.

Conclusion

The GO-CAM model "Liver apoptosis regulation by CASP6 (Human)" effectively represents the key molecular interactions in the AMPK-CASP6-BID pathway involved in liver damage during NASH. It is well-supported by published evidence and follows GO-CAM best practices. With the suggested enhancements, the model could more comprehensively capture the molecular details and feedback mechanisms involved in this important pathway.

The model makes a valuable contribution to understanding how metabolic dysregulation in NASH leads to increased hepatocyte apoptosis through the AMPK-CASP6 axis, which has been identified as a potential therapeutic target for NASH treatment.