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Based on all the information gathered, I'll now provide a comprehensive review of gomodel:627d95ee00001405, which is titled "IL17A mediated signaling pathway (Human)".

GO-CAM Model Review: IL17A mediated signaling pathway (Human)

Model ID

gomodel:627d95ee00001405

Overview

This model represents the interleukin 17A-mediated signaling pathway in humans, including a component on how SARS-CoV-2 ORF8 protein interferes with this pathway. The model includes seven distinct molecular activities from different proteins that form the IL-17 signaling cascade.

Biological Accuracy

The model accurately represents the current understanding of IL-17 signaling as described in the literature:

  1. IL-17A (UniProtKB:Q16552) acts as a cytokine (GO:0005125) in the extracellular space (GO:0005615), which is consistent with its known role.

  2. IL-17RA (UniProtKB:Q96F46) functions as an IL-17 receptor (GO:0030368) at the plasma membrane (GO:0005886), which correctly represents its biological location and function.

  3. IL-17RC (UniProtKB:Q8NAC3) serves as a coreceptor (GO:0015026), also at the plasma membrane, which is supported by literature showing IL-17A signals through a heterodimeric complex of IL-17RA and IL-17RC.

  4. The model correctly shows the subsequent signaling cascade involving TRAF3IP2 (Act1), TRAF6, and MAP3K7 (TAK1) with their respective molecular functions.

  5. The SARS-CoV-2 ORF8 (UniProtKB:P0DTC8) is included with cytokine activity (GO:0005125) as part of a virus-mediated perturbation of host defense response (GO:0019049), which is supported by recent research showing how ORF8 can mimic IL-17A and activate the IL-17 pathway.

Causal Relations

The model includes appropriate causal relations between activities:

  1. IL-17A and SARS-CoV-2 ORF8 both causally regulate IL-17RA through RO:0002629 (directly positively regulates) and RO:0002413 (provides input for) relationships, accurately representing how both proteins can activate the receptor.

  2. IL-17RA correctly regulates IL-17RC using RO:0002629, showing receptor complex formation.

  3. IL-17RC regulates TRAF3IP2 using RO:0002629, which then regulates TRAF6 with the same predicate.

  4. TRAF6 regulates MAP3K7 with RO:0002629, completing the signaling cascade.

All these causal relations are consistent with the known biology of IL-17 signaling.

GO-CAM Best Practices Compliance

  1. Molecular function annotations: Each protein has the appropriate molecular function assignment with supporting evidence and references.

  2. Cellular component annotations: All proteins have appropriate cellular location annotations.

  3. Biological process annotations: Each activity is properly contextualized in its biological process.

  4. Evidence: All activities and causal relations include evidence codes with appropriate PMIDs, mostly using ECO:0000314 (direct assay evidence) which is appropriate.

  5. Causal relations: The model uses the correct causal relation predicates (RO:0002629 for direct positive regulation and RO:0002413 for providing input).

  6. Directionality: The flow of information in the pathway proceeds in the correct direction.

Comments on Specific Model Features

SARS-CoV-2 ORF8 inclusion

The inclusion of SARS-CoV-2 ORF8 (P0DTC8) is supported by recent literature (PMID:33723527) which shows that ORF8 can mimic IL-17A by binding to IL-17RA and activating the pathway. The representation of ORF8 as having cytokine activity is consistent with its functional role, though it's worth noting this is a case of viral mimicry rather than a true cytokine.

Receptor activation

The model correctly represents that both IL-17A and SARS-CoV-2 ORF8 can activate IL-17RA, with IL-17A being the physiological ligand and ORF8 being a viral mimic. The use of both RO:0002629 (directly positively regulates) and RO:0002413 (provides input for) relationships from ORF8 to IL-17RA appears redundant, as one relationship would suffice to indicate the causal connection.

IL-17RA and IL-17RC interaction

The model correctly represents IL-17RC as a coreceptor that works with IL-17RA. According to the literature, IL-17A binds to a heterodimeric receptor complex composed of IL-17RA and IL-17RC. The causal relationship from IL-17RA to IL-17RC (RO:0002629) is appropriate to represent this functional relationship.

Signaling cascade

The downstream signaling events are accurately represented, showing the recruitment and activation of TRAF3IP2 (Act1), which then activates TRAF6, which in turn activates MAP3K7 (TAK1). This is consistent with the canonical IL-17 signaling pathway described in the literature.

Areas for Improvement

  1. Redundant causal relations: There are two identical causal relationships from ORF8 to IL-17RA using the RO:0002413 predicate. One of these should be removed as it's redundant.

  2. Receptor complex representation: While the model correctly shows IL-17RA and IL-17RC with their respective activities, according to the GO-CAM guidelines for annotating complexes, the heterodimeric nature of the IL-17 receptor complex could be more explicitly represented. Since both proteins contribute to receptor function, this could be considered a case where "the activity is shared by several proteins."

  3. Downstream effects: The model stops at MAP3K7 (TAK1) activation. It could be expanded to include downstream transcription factors and the resulting gene expression changes that lead to the pro-inflammatory effects of IL-17 signaling.

  4. Feedback mechanisms: The model doesn't include any negative feedback mechanisms that regulate IL-17 signaling, which could enhance the biological completeness of the representation.

Conclusion

Overall, gomodel:627d95ee00001405 is a well-constructed GO-CAM that accurately represents the IL-17A signaling pathway in humans, with the interesting addition of SARS-CoV-2 ORF8 as a viral mimic of IL-17A. The model follows GO-CAM best practices for the most part, with appropriate molecular functions, cellular components, biological processes, and causal relations.

The main recommendations for improvement would be to: 1. Remove the redundant causal relation from ORF8 to IL-17RA 2. Consider enhancing the representation of the IL-17RA/IL-17RC heterodimeric complex 3. Extend the model to include downstream transcription factors and gene expression changes 4. Add negative feedback mechanisms to provide a more comprehensive view of pathway regulation

This model provides valuable insights into both normal IL-17 signaling and how SARS-CoV-2 may hijack this pathway to contribute to cytokine storm during infection, which is a significant finding with clinical implications.