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645d887900001414 ZNFR1 mediated TLR4 signaling pathway via CAV1 ubiquitination and degradation Human

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Based on all the information I've collected, I can provide a comprehensive review of the GO-CAM model with ID 645d887900001414 titled "ZNFR1-mediated TLR4 signaling pathway via CAV1 ubiquitination and degradation (Human)".

GO-CAM Model Review: ZNFR1-mediated TLR4 signaling pathway via CAV1 ubiquitination and degradation (Human)

Summary of the Model

This model describes how the E3 ubiquitin ligase ZNRF1 regulates TLR4 signaling by mediating the ubiquitination and degradation of Caveolin-1 (CAV1). The model captures how ZNRF1's E3 ligase activity negatively regulates CAV1's protein sequestering activity, which in turn affects TLR4 signaling receptor activity and downstream signaling through MYD88 (molecular adaptor) to PIK3R1 (phosphatidylinositol kinase activity).

Biological Accuracy

  1. Main Mechanism Assessment: The model accurately captures the key findings from the literature (particularly from PMID:28593998), which shows that ZNRF1 promotes CAV1 ubiquitination and degradation to modulate TLR4-driven immune responses. The causal relationships correctly show that ZNRF1's E3 ubiquitin ligase activity directly negatively regulates CAV1's sequestering activity.

  2. Molecular Functions:

  3. ZNRF1 (Q8ND25) is correctly annotated with E3 ubiquitin-protein ligase activity (GO:0061630), which is supported by direct experimental evidence.
  4. CAV1 (Q03135) is correctly annotated with protein sequestering activity (GO:0140311), which is well-documented in its role of sequestering signaling molecules.
  5. TLR4 (O00206) is correctly annotated with signaling receptor activity (GO:0038023).
  6. MYD88 (Q99836) is correctly annotated with molecular adaptor activity (GO:0060090), which aligns with its well-known role in TLR signaling.

  7. PIK3R1 (P27986) is appropriately annotated with phosphatidylinositol kinase activity (GO:0052742).

  8. Causal Relationships: The causal relationships are represented appropriately using:

  9. RO:0002630 (directly negatively regulates) from ZNRF1 activity to CAV1 activity
  10. RO:0002630 (directly negatively regulates) from CAV1 activity to TLR4 activity
  11. RO:0002629 (directly positively regulates) from TLR4 activity to MYD88 activity
  12. RO:0002629 (directly positively regulates) from MYD88 activity to PIK3R1 activity

Technical Correctness

  1. Evidence and Citations: The model includes appropriate evidence codes and literature citations:
  2. ECO:0000314 (direct assay evidence used in manual assertion) is used for most activities
  3. PMID:28593998 is correctly cited for ZNRF1's ubiquitination of CAV1

  4. Other literature citations appear appropriate for the respective components

  5. Cellular Location: The subcellular locations are correctly annotated:

  6. ZNRF1 and CAV1 are correctly located at the plasma membrane (GO:0005886)
  7. TLR4 is correctly annotated as occurring at the plasma membrane
  8. MYD88 is appropriately located at the plasma membrane

  9. PIK3R1 is correctly located in the cytoplasm (GO:0005737)

  10. Process Context: Each activity is appropriately placed in its biological process context:

  11. ZNRF1 activity is part of the positive regulation of TLR4 signaling pathway (GO:0034145)
  12. CAV1 activity is part of the negative regulation of TLR4 signaling pathway (GO:0034144)
  13. TLR4 activity is part of the TLR4 signaling pathway (GO:0034142)
  14. MYD88 activity is part of the TLR4 signaling pathway (GO:0034142)
  15. PIK3R1 activity is part of the regulation of TLR4 signaling pathway (GO:0034143)

Suggestions for Improvement

  1. Include Ubiquitination Site: The model could specify the specific lysine residue (Lys-39) on CAV1 that is targeted by ZNRF1 for ubiquitination, as mentioned in the literature.

  2. Additional Downstream Effects: The model could be extended to include the downstream effects on the Akt-GSK3β pathway that was mentioned in the paper as a mechanism by which the ZNRF1-CAV1 axis regulates TLR4 signaling.

  3. Inflammatory Cytokine Production: The model could potentially include the end result of this pathway - the production of pro-inflammatory cytokines and inhibition of anti-inflammatory cytokine IL-10, which are important outcomes of this signaling pathway.

  4. LPS as Stimulus: The model could explicitly represent lipopolysaccharide (LPS) as the activating stimulus for this pathway, as ZNRF1 was shown to interact with CAV1 in response to LPS.

Conclusion

The GO-CAM model 645d887900001414 is a technically solid representation of the ZNRF1-mediated regulation of TLR4 signaling through CAV1 ubiquitination and degradation. It accurately captures the main molecular activities, causal relationships, and cellular locations based on published literature. The model effectively represents this important regulatory mechanism in innate immune signaling.

The model is consistent with best practices for GO-CAM curation, including proper annotation of molecular functions, biological processes, cellular components, and causal relationships. The evidence codes and citations are appropriately used throughout the model.

While some additional details could be incorporated to make the model more comprehensive, such as specific ubiquitination sites and downstream effects, the current representation provides a clear and accurate view of this regulatory mechanism in TLR4 signaling.