Skip to content

Based on the information gathered, I can now provide a comprehensive review of the GO-CAM model gomodel:64d5781900000111.

Review of GO-CAM Model: gomodel:64d5781900000111

Model Overview

Model ID: 64d5781900000111
Title: Activation of cGAS-STING signaling following acetylation by KAT5 (Human)
Taxon: Human (NCBITaxon:9606)
Status: Production

Summary of the Model Content

This model represents the activation pathway of the cGAS-STING signaling cascade in humans, specifically focusing on how KAT5-mediated acetylation of cGAS enhances the innate immune response to DNA viruses. The model includes three main proteins:

  1. cGAS (UniProtKB:Q8N884) - Cyclic GMP-AMP synthase, the cytosolic DNA sensor
  2. KAT5 (UniProtKB:Q92993-4) - Histone acetyltransferase, which acetylates cGAS
  3. CGAS-STING pathway (GO:0140896)

The model includes the following molecular activities and causal relationships: - KAT5 has peptide-lysine-N-acetyltransferase activity (GO:0061733) - KAT5 acetylates cGAS, which directly positively regulates cGAS DNA binding - cGAS has double-stranded DNA binding activity (GO:0003690) - cGAS DNA binding directly positively regulates cGAS's molecular condensate scaffold activity (GO:0140693) - cGAS has 2',3'-cyclic GMP-AMP synthase activity (GO:0061501)

Review Findings

Structural Accuracy

The model correctly captures the key sequential elements of the cGAS activation pathway: 1. KAT5 acetylates cGAS 2. Acetylated cGAS binds to double-stranded DNA 3. DNA binding enhances cGAS's ability to act as a molecular condensate scaffold 4. cGAS produces 2',3'-cyclic GMP-AMP, activating the STING pathway

Evidence Support

The model is well-supported by scientific evidence, with all activities backed by experimental evidence: - All assertions are supported by experimental evidence (ECO:0000314 - direct assay evidence used in manual assertion) - The model cites multiple peer-reviewed publications: PMID:32911482, PMID:32912999, PMID:31544964, PMID:32817552, PMID:30842659, PMID:30842662, and PMID:17360565 - The evidence aligns with current understanding of cGAS activation

Biological Accuracy

The model is consistent with the current scientific understanding of cGAS activation as described in the cited literature. The cited papers provide strong evidence for:

  1. The acetylation of cGAS by KAT5 (PMID:32817552)
  2. The importance of DNA binding for cGAS activation (PMID:32911482, PMID:32912999)
  3. The formation of molecular condensates by cGAS upon DNA binding (PMID:32911482)
  4. The connection between these activities and the cGAS-STING signaling pathway (PMID:31544964)

GO-CAM Best Practices

The model follows GO-CAM best practices:

  1. Causal relationships: The model properly uses RO:0002629 (directly positively regulates) to connect the activities in the causal chain.

  2. Cellular location: All activities correctly specify their cellular locations (nucleus - GO:0005634).

  3. Molecular activities: The model appropriately assigns molecular functions to each protein - peptide-lysine-N-acetyltransferase activity to KAT5, and double-stranded DNA binding, molecular condensate scaffold activity, and 2',3'-cyclic GMP-AMP synthase activity to cGAS.

  4. Part-of relations: Activities are correctly connected to the biological process "cGAS/STING signaling pathway" (GO:0140896) using part_of relations.

Areas for Potential Improvement

While the model is accurate and well-constructed, there are a few areas that could be enhanced:

  1. Specific acetylation sites: The model could be more specific about which lysine residues of cGAS are acetylated by KAT5. According to PMID:32817552, KAT5 acetylates specific lysine residues in the N-terminus of cGAS (K47, K56, K62, and K83). Adding this information would increase the model's precision.

  2. Molecular mechanism details: The model could potentially include additional details about how acetylation enhances DNA binding, such as by explaining that acetylation of N-terminal lysines increases the DNA binding affinity of cGAS.

  3. Downstream effects: While the model shows the activation of cGAS's 2',3'-cyclic GMP-AMP synthase activity, it doesn't show the production of cGAMP and its effects on STING. Including these downstream steps would make the model more complete.

  4. Nuclear localization vs. cytosolic activity: Recent literature suggests that cGAS can be found in both the nucleus (bound to nucleosomes, which inhibits its activity) and the cytosol (where it's activated by foreign DNA). The model shows all activities occurring in the nucleus, but it might be more accurate to indicate that while cGAS is found in the nucleus, its actual DNA-sensing activity against viral DNA typically occurs in the cytosol.

Conclusion

GO-CAM model 64d5781900000111 is a scientifically accurate and well-constructed representation of the KAT5-mediated activation of cGAS in the cGAS-STING signaling pathway. The model appropriately uses GO terms and relations to capture the causal relationships between molecular activities, and is well-supported by experimental evidence from peer-reviewed publications.

The model correctly captures how KAT5 acetylates cGAS, which enhances cGAS's ability to bind double-stranded DNA, form molecular condensates, and synthesize 2',3'-cyclic GMP-AMP to activate the STING pathway. This pathway is crucial for innate immune responses to DNA viruses and cytosolic self-DNA.

With a few minor enhancements to include more specific details about acetylation sites and subcellular location of activities, this model would provide an even more comprehensive representation of this important signaling pathway.