Skip to content

Based on my review of the GO-CAM model "6413ac9800000256" titled "MYD88-dependent TLR4 signaling pathway leading to autophagy activation (Human)" and the relevant literature, I'll now provide a comprehensive review:

GO-CAM Model Review: gomodel:6413ac9800000256

Model Overview

This model represents the MYD88-dependent TLR4 signaling pathway leading to autophagy activation in humans. It captures a signaling cascade from TLR4 receptor activity at the plasma membrane through a series of molecular adaptors and kinases, ultimately resulting in autophagosome assembly through phosphatidylinositol 3-kinase activity.

Pathway Structure and Flow

The model shows the following causal chain: 1. TLR4 (O00206) signaling receptor activity at plasma membrane → 2. TIRAP (P58753) molecular adaptor activity → 3. MYD88 (Q99836) molecular adaptor activity → 4. IRAK4 (Q9NWZ3) protein serine/threonine kinase activity → 5. IRAK2 (O43187) molecular adaptor activity → 6. TRAF6 (Q9Y4K3) ubiquitin protein ligase activity → 7. BECN1 (Q14457) molecular adaptor activity → 8. PIK3C3/VPS34 (Q8NEB9) phosphatidylinositol kinase activity

The model correctly uses the causal relation RO:0002629 (directly positively regulates) for all connections in the pathway, creating a coherent signal flow from the plasma membrane receptor to autophagosome assembly.

Strengths of the Model

  1. Biological accuracy: The model correctly captures the known signaling pathway from TLR4 activation to autophagy, supported by literature including PMID:33637724 which describes VPS34's role in autophagosome formation.

  2. Subcellular localization: Each activity is appropriately associated with a cellular location (plasma membrane for receptors, cytoplasm for downstream components).

  3. Evidence: All activities and causal relationships are supported by appropriate literature evidence using ECO codes.

  4. Consistent use of causal relations: The model appropriately uses RO:0002629 (directly positively regulates) for adjacent steps in the pathway.

  5. Process contextualization: Activities are properly contextualized within biological processes (e.g., TLR4 signaling pathway, autophagosome assembly).

Areas for Improvement

  1. Missing lipopolysaccharide input: While CHEBI:16412 (lipopolysaccharide) is listed in the objects, it's not shown as the initiating input for TLR4 activation. A causal relation showing LPS providing input to TLR4 would improve the model.

  2. Additional pathway branches: The model focuses on a single linear pathway, but TLR4 signaling typically branches to multiple downstream targets. If evidence exists, the model could be expanded to show additional branches.

  3. Molecular complex representation: According to the "How to annotate complexes in GO-CAM" document, if specific subunits carrying molecular activities are known (as in this case), they should be represented directly. The model correctly does this, but it might be helpful to also indicate which proteins form functional complexes.

  4. Specific mechanism details: For TRAF6's regulation of BECN1, additional mechanistic details could be added. From the PMID:33637724 paper, we know that ubiquitination plays a key role in this regulation.

  5. Feedback regulation: The model doesn't capture any potential feedback regulation mechanisms that might exist in this pathway, which could be added if supported by evidence.

Accuracy of Individual Components

  1. PIK3C3/VPS34 (Q8NEB9): The representation as having phosphatidylinositol kinase activity and being involved in autophagosome assembly is accurate and supported by UniProt information and the literature (PMID:33637724).

  2. TLR4 signaling components: The representation of the TLR4 signaling cascade through TIRAP, MYD88, IRAK4, IRAK2, and TRAF6 is consistent with established knowledge of this pathway.

  3. BECN1's role: The model correctly positions BECN1 as a molecular adaptor in autophagy, which is consistent with its known function in the VPS34 complex.

Conclusion

This is a well-constructed GO-CAM model that accurately represents the MYD88-dependent TLR4 signaling pathway leading to autophagy activation. It correctly captures the key molecular functions, cellular locations, and causal relationships in this pathway. The model could be enhanced by explicitly showing the LPS trigger and potentially expanding to include additional pathway branches or feedback mechanisms. Overall, the model meets GO-CAM best practices and provides a valuable representation of this important cellular signaling pathway.