Skip to content

Based on my review of the model and the related documentation, let me provide a comprehensive review of GO-CAM model 646ff70100005137 (IL33-signaling pathway in Human).

Review of GO-CAM model: IL33-signaling pathway (Human)

GO-CAM Overview

Model ID: gomodel:646ff70100005137
Title: IL33-signaling pathway (Human)
Taxon: Human (NCBITaxon:9606)
Status: Production

General Assessment

This model represents the IL33-signaling pathway in humans, depicting how IL-33 activates the IL-33 receptor complex (consisting of IL1RL1 and IL1RAP) and the downstream signaling cascade. The model follows a well-structured approach to explain the signal transduction from IL-33 cytokine binding to the activation of downstream effectors.

Strengths

  1. The model correctly captures the IL-33 signaling pathway showing the proper sequence of activation events from cytokine to receptor to downstream signaling components.

  2. The model appropriately uses the "directly positively regulates" predicate (RO:0002629) for causal connections between activities, which is consistent with GO-CAM best practices.

  3. Each activity has been properly contextualized with appropriate cellular locations (CC), biological processes (BP), and molecular functions (MF).

  4. All elements are backed by appropriate evidence codes and literature references, primarily from published papers.

Points for Improvement

  1. Adaptor protein annotation: MYD88 is annotated with "molecular adaptor activity" (GO:0060090) which is correct, but according to the document "How to annotate molecular adaptors", MYD88 should have both IL1RL1 and IRAK4 as inputs. Currently, only one causal connection is modeled showing MYD88 directly positively regulating IRAK4 kinase activity.

  2. Receptor-coreceptor annotation: While the model correctly shows IL1RAP as a coreceptor with "coreceptor activity" (GO:0015026), the "Signaling receptor activity annotation guidelines" suggest that there should be a causal relationship between the receptor (IL1RL1) and coreceptor (IL1RAP). Currently, there are two separate causal connections from IL1RAP to MYD88.

  3. Redundant causal links: IL1RAP appears to have two identical causal connections to MYD88 (both are RO:0002629 "directly positively regulates"). One of these is likely redundant.

  4. Pathway completion: The model captures the pathway from IL33 through MAP3K7 (TAK1) but doesn't show the final downstream effects (e.g., activation of transcription factors or gene expression). While this is not necessarily incorrect, extending the model to show these endpoints would provide a more complete representation.

Detailed Annotation Review

IL-33 (UniProtKB:O95760)

  • MF: cytokine activity (GO:0005125) ✓
  • CC: extracellular space (GO:0005615) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • Causal association: directly positively regulates IL1RL1 ✓
  • Evidence: ECO:0000314 (direct assay evidence), PMID:27830702 ✓

IL1RL1 (UniProtKB:Q01638)

  • MF: cytokine receptor activity (GO:0004896) ✓
  • CC: plasma membrane (GO:0005886) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • Causal association: directly positively regulates IL1RAP ✓
  • Evidence: ECO:0000304 (author statement), PMID:10191101 ✓

IL1RAP (UniProtKB:Q9NPH3)

  • MF: coreceptor activity (GO:0015026) ✓
  • CC: plasma membrane (GO:0005886) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • Causal association: directly positively regulates MYD88 (two identical connections) ❗
  • Evidence: ECO:0000304 (author statement), PMID:10191101 ✓

MYD88 (UniProtKB:Q99836)

  • MF: molecular adaptor activity (GO:0060090) ✓
  • CC: cytoplasm (GO:0005737) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • Causal association: directly positively regulates IRAK4 ✓
  • Evidence: ECO:0000314 (direct assay evidence), PMID:16751103 ✓
  • Missing inputs: Should have both IL1RL1 and IRAK4 as inputs according to the molecular adaptor guidelines ❗

IRAK4 (UniProtKB:Q9NWZ3)

  • MF: protein serine/threonine kinase activity (GO:0004674) ✓
  • CC: cytoplasm (GO:0005737) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • Causal association: directly positively regulates IRAK1 ✓
  • Evidence: ECO:0000314 (direct assay evidence), PMID:11960013 ✓

IRAK1 (UniProtKB:P51617)

  • MF: protein serine/threonine kinase activity (GO:0004674) ✓
  • CC: cytoplasm (GO:0005737) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • Causal association: directly positively regulates TRAF6 ✓
  • Evidence: ECO:0000314 (direct assay evidence), PMID:14625308 ✓

TRAF6 (UniProtKB:Q9Y4K3)

  • MF: ubiquitin protein ligase activity (GO:0061630) ✓
  • CC: cytoplasm (GO:0005737) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • Causal association: directly positively regulates MAP3K7 ✓
  • Evidence: ECO:0000314 (direct assay evidence), PMID:18758450 ✓

MAP3K7 (UniProtKB:O43318)

  • MF: MAP kinase activity (GO:0004707) ✓
  • CC: cytoplasm (GO:0005737) ✓
  • BP: interleukin-33-mediated signaling pathway (GO:0038172) ✓
  • No downstream causal links ❗

Literature Support

The model is well supported by appropriate literature references. Key references like PMID:27830702 and PMID:16286016 appropriately describe the IL-33 signaling pathway and the role of IL1RL1 (ST2) as the primary receptor for IL-33.

The referenced paper (PMID:27830702) confirms IL-33's role in activating ST2 (IL1RL1) and IL1RAP to mediate downstream signaling. The paper also supports the involvement of MYD88, IRAK4, and TRAF6 in this pathway, consistent with the model.

Recommendations

  1. Add missing inputs for MYD88: According to the molecular adaptor guidelines, MYD88 should have both IL1RL1 and IRAK4 as inputs.

  2. Resolve redundant causal links: Remove one of the duplicate causal associations from IL1RAP to MYD88.

  3. Add a direct causal link between IL1RL1 and IL1RAP: According to the signaling receptor activity guidelines, there should be a causal relationship between the receptor (IL1RL1) and coreceptor (IL1RAP).

  4. Extend the pathway downstream: Consider extending the model to include the downstream effects of MAP3K7 activation, such as the activation of NF-κB and/or MAP kinases, and the resulting gene expression changes.

  5. Add additional supporting evidence: While the current evidence is solid, adding more recent papers could strengthen the model further, especially for the downstream components.

Conclusion

Overall, this GO-CAM model provides a good representation of the IL-33 signaling pathway in humans. It follows most of the GO-CAM best practices and is supported by appropriate literature references. With the suggested improvements, particularly regarding the adaptor protein annotation and the receptor-coreceptor relationship, the model would more accurately represent the biology of IL-33 signaling according to current knowledge and GO-CAM guidelines.