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Based on the information I've gathered, I'll now provide a comprehensive review of the GO-CAM model gomodel:627d95ee00000757 "Regulation of CGAS activity by ZDHHC18 (Human)".

Review of GO-CAM Model: Regulation of CGAS activity by ZDHHC18 (Human)

Model Information

  • Model ID: gomodel:627d95ee00000757
  • Title: Regulation of CGAS activity by ZDHHC18 (Human)
  • Taxon: Human (NCBITaxon:9606)
  • Status: Production

Model Overview

This GO-CAM model represents the regulation of cyclic GMP-AMP synthase (cGAS) activity by the protein palmitoyltransferase ZDHHC18 in humans. The model shows a negative regulatory relationship where ZDHHC18's palmitoyltransferase activity directly negatively regulates cGAS's double-stranded DNA binding activity, which in turn directly positively regulates cGAS's molecular condensate scaffold activity.

Model Structure

The model includes three activities:

  1. ZDHHC18 protein-cysteine S-palmitoyltransferase activity:
  2. Enabled by: UniProtKB:Q9NUE0 (ZDHHC18)
  3. Occurs in: GO:0005794 (Golgi apparatus)
  4. Part of: GO:0160049 (negative regulation of cGAS/STING signaling pathway)

  5. Causal relationship: RO:0002630 (directly negatively regulates) → cGAS DNA binding activity

  6. cGAS double-stranded DNA binding activity:

  7. Enabled by: UniProtKB:Q8N884 (cGAS)
  8. Occurs in: GO:0005829 (cytosol)
  9. Part of: GO:0140896 (cGAS/STING signaling pathway)

  10. Causal relationship: RO:0002629 (directly positively regulates) → cGAS molecular condensate scaffold activity

  11. cGAS molecular condensate scaffold activity:

  12. Enabled by: UniProtKB:Q8N884 (cGAS)
  13. Occurs in: GO:0005829 (cytosol)
  14. Part of: GO:0140896 (cGAS/STING signaling pathway)

Evidence

The model is supported by experimental evidence from two publications: 1. PMID:35438208 - Evidence for ZDHHC18's palmitoyltransferase activity and its regulatory effect on cGAS 2. PMID:32912999 - Evidence for cGAS's molecular condensate scaffold activity

Biological Context

Based on the literature and UniProt entries:

  1. ZDHHC18 is a palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, including cGAS. It acts as a negative regulator of the cGAS-STING pathway by mediating palmitoylation and inactivation of cGAS.

  2. cGAS is a key DNA sensor in innate immunity. Upon binding to cytosolic double-stranded DNA, cGAS forms liquid-like phase-separated condensates (represented by the molecular condensate scaffold activity) which facilitate its enzymatic activity to produce cyclic GMP-AMP (cGAMP). This second messenger then activates the STING pathway, leading to type I interferon production.

  3. The model captures how ZDHHC18 negatively regulates cGAS activity through palmitoylation, specifically at Cys-474 of cGAS (as indicated in the UniProt entry), which impairs DNA-binding and prevents its activation.

Assessment of Model Quality

Strengths:

  1. Accurate representation of biological knowledge: The model correctly represents the negative regulatory relationship between ZDHHC18 and cGAS, which is supported by the literature.

  2. Appropriate use of GO terms: The molecular functions and cellular locations are appropriate for the proteins involved.

  3. Correct causal relationships: The model uses appropriate causal predicates (RO:0002630 for negative regulation and RO:0002629 for positive regulation).

  4. Evidence-based: All activities and relationships are supported by published experimental evidence.

Suggestions for Improvement:

  1. Molecular mechanism details: The model could benefit from including information about the specific site of palmitoylation on cGAS (Cys-474) that ZDHHC18 targets.

  2. Complete pathway representation: The model captures the initial regulatory events but doesn't extend to the downstream consequences of cGAS inhibition on the STING pathway and type I interferon production.

  3. Additional activities: The model doesn't include the cyclic GMP-AMP synthase activity of cGAS (GO:0061501), which is the primary enzymatic function affected by this regulation.

Compliance with GO-CAM Best Practices

The model follows GO-CAM best practices by: - Using appropriate GO terms for molecular functions - Correctly using causal relationship predicates - Properly representing cellular locations of activities - Including evidence from the literature - Maintaining a parsimonious structure that is easy to understand

Conclusion

The GO-CAM model "Regulation of CGAS activity by ZDHHC18 (Human)" provides an accurate representation of how ZDHHC18 negatively regulates cGAS activity through its palmitoyltransferase activity. The model is well-structured, evidence-based, and follows GO-CAM best practices. It could be enhanced by including more details about the specific palmitoylation site and downstream effects on the cGAS-STING signaling pathway. Overall, this is a high-quality model that effectively captures an important regulatory mechanism in innate immunity.