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Based on all the information I've gathered, I will now provide a detailed review of the GO-CAM model gomodel:627d95ee00000909 which represents "Regulation of CGAS by PCBP2 (Human)".

Review of GO-CAM Model: 627d95ee00000909 - Regulation of CGAS by PCBP2 (Human)

Model Overview

This GO-CAM model describes the regulatory mechanism by which PCBP2 (Poly(rC)-binding protein 2) negatively regulates cGAS (Cyclic GMP-AMP synthase) activity in human cells. The model consists of three activities:

  1. PCBP2 protein binding activity (GO:0005515) that directly negatively regulates cGAS
  2. cGAS molecular condensate scaffold activity (GO:0140693)
  3. cGAS 2',3'-cyclic GMP-AMP synthase activity (GO:0061501)

All these activities are part of the cGAS/STING signaling pathway (GO:0140896) with the first activity also being part of negative regulation of cGAS/STING signaling pathway (GO:0160049).

Scientific Assessment

The model accurately represents the findings from the primary literature (PMID:35322803), which demonstrates that PCBP2 negatively regulates cGAS by: 1. Directly interacting with cGAS 2. Preventing cGAS condensation (phase separation) 3. Reducing cGAS enzymatic activity

This interaction prevents excessive immune activation by maintaining homeostatic control of the cGAS-STING signaling pathway.

The publication provides strong experimental evidence for this interaction, including co-immunoprecipitation experiments, in vitro binding assays, and functional assays showing that PCBP2 overexpression reduces cGAS-mediated interferon production while PCBP2 deficiency enhances it.

Model Structure and Annotation Assessment

Strengths:

  1. The model correctly uses "directly negatively regulates" (RO:0002630) for the relationship between PCBP2 and cGAS activities
  2. The protein binding activity of PCBP2 is appropriately linked to its regulatory function
  3. The model captures both the molecular condensate scaffold activity and the enzymatic activity of cGAS
  4. The evidence is properly cited with references to the primary literature (PMID:35322803)
  5. The model captures the correct biological context (cGAS/STING signaling pathway)

Issues and Recommendations:

  1. Redundant causal links: The model contains duplicate causal associations from PCBP2 to cGAS molecular condensate scaffold activity. This represents a technical error in the model structure.

  2. Recommendation: Remove one of the duplicate "directly negatively regulates" (RO:0002630) links between PCBP2 and cGAS activities.

  3. Molecular Details: While the model correctly shows that PCBP2 inhibits cGAS, it could more specifically represent the mechanism of inhibition via preventing phase separation.

  4. Recommendation: Consider adding more details about the mechanism of inhibition, such as specifying that PCBP2 binds to the C-terminal domain of cGAS to prevent its condensation.

  5. Input/Output Relationships: The model doesn't explicitly represent the relationship between cGAS's scaffold activity and its enzymatic activity.

  6. Recommendation: Consider adding a causal link between the molecular condensate scaffold activity (GO:0140693) and the 2',3'-cyclic GMP-AMP synthase activity (GO:0061501) of cGAS, as the paper shows that phase separation/condensation is important for cGAS enzymatic activity.

  7. Biological Context: The model accurately places activities in the cGAS/STING signaling pathway but could further specify the context of DNA-sensing.

  8. Recommendation: Consider adding information about DNA binding as an input to cGAS activities to more completely represent the biological context.

  9. Additional Insights from Other Papers: The second paper (PMID:33542149) provides insights about regulation of cGAS during mitosis that could enhance the model.

  10. Recommendation: If expanding the model, consider adding information about how chromatin tethering and phosphorylation regulate cGAS activity during the cell cycle.

Compliance with GO-CAM Standards

The model generally follows GO-CAM annotation standards for regulatory processes. The use of "directly negatively regulates" is appropriate given the direct physical interaction between PCBP2 and cGAS shown in the paper.

According to the "WIP - Regulation and Regulatory Processes in GO-CAM" guidelines, regulatory activities should capture the specific mechanism, which this model does by representing PCBP2's protein binding activity as the regulatory mechanism.

Overall Assessment

This is a well-constructed GO-CAM model that accurately captures the findings from the primary literature about PCBP2's role in regulating cGAS activity. The main area for improvement is the technical error of duplicate causal links. Additionally, the model could be enriched with more specific details about the molecular mechanism of inhibition, though this would be considered an enhancement rather than a necessary correction.

The model is biologically sound, with activities assigned to the correct gene products and appropriate causal relationships between activities. The evidence is properly cited, and the biological process context is accurate.

Summary

This GO-CAM model provides a valuable representation of a negative regulatory mechanism in the cGAS/STING signaling pathway, which is important for innate immune responses against DNA viruses and maintenance of immune homeostasis. With minor corrections and potential enhancements, it will serve as an excellent resource for understanding how PCBP2 regulates cGAS activity.