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Based on all the information I've gathered, I'll now proceed with a comprehensive review of the GO-CAM model gomodel:663d668500000226.

Review of GO-CAM Model gomodel:663d668500000226

Model Summary

Title: VIF-mediated inhibition of STING by PTPN6 (Human-HIV)
ID: gomodel:663d668500000226
Taxon: Human (NCBITaxon:9606)
Status: Production

Overall Model Evaluation

This GO-CAM model describes a mechanism by which HIV-1 viral infectivity factor (Vif) promotes immune evasion by inhibiting the STING-mediated antiviral immune response. The model shows how Vif acts as a molecular adaptor to recruit the tyrosine phosphatase PTPN6 (SHP-1) to inhibit STING1 activity, thereby suppressing type I interferon production.

Model Strengths:

  1. Well-supported by recent literature (PMID:34811497).
  2. Clear logical flow showing the causal relationships between molecular activities.
  3. Appropriate use of GO terms for molecular functions and biological processes.
  4. Properly annotated with evidence codes and PMID references.

Model Structure and Connectivity:

The model presents five connected activities: 1. FRK kinase activity - activates Vif adaptor protein 2. Vif adaptor activity - recruits PTPN6 (SHP-1) 3. PTPN6 phosphatase activity - dephosphorylates STING 4. STING adaptor activity - inhibited by PTPN6 dephosphorylation 5. TBK1 kinase activity - downstream of STING (not directly shown)

The causal flow is logical, with "provides input for" and "directly negatively regulates" relations correctly used according to GO-CAM best practices.

Detailed Component Analysis

1. Vif Molecular Adaptor Activity

  • MF: protein-macromolecule adaptor activity (GO:0030674)
  • Enabled by: Vif protein (UniProtKB:P69723)
  • Occurs in: host cell cytoplasm (GO:0030430)
  • Part of: symbiont-mediated suppression of cytoplasmic pattern recognition receptor signaling pathway (GO:0039537)
  • Evidence: Direct assay evidence (ECO:0000314, PMID:34811497)
  • Causal connection: provides input for PTPN6 phosphatase activity

This annotation is consistent with the documented molecular adaptor activity guidelines. According to the Wang et al. (2021) paper, Vif contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) that, when phosphorylated by FRK, recruits PTPN6/SHP-1 to inhibit STING signaling.

2. PTPN6 Phosphatase Activity

  • MF: protein tyrosine phosphatase activity (GO:0004725)
  • Enabled by: PTPN6/SHP-1 (UniProtKB:P29350)
  • Occurs in: cytoplasm (GO:0005737)
  • Part of: negative regulation of innate immune response (GO:0045824)
  • Evidence: Mutant phenotype evidence (ECO:0000315, PMID:17562706)
  • Causal connection: directly negatively regulates STING adaptor activity

The annotation correctly captures PTPN6's role in dephosphorylating STING, which is supported by the literature. The causal relationship is properly represented with "directly negatively regulates" since PTPN6 inhibits STING's function.

3. FRK Kinase Activity

  • MF: protein tyrosine kinase activity (GO:0004713)
  • Enabled by: FRK (UniProtKB:P42685)
  • Occurs in: cytoplasm (GO:0005737)
  • Evidence: Direct assay evidence (ECO:0000314, PMID:35723276)
  • Causal connection: directly positively regulates Vif adaptor activity

This annotation correctly represents FRK's role in phosphorylating the ITIM motif of Vif, which enables Vif to recruit PTPN6.

4. STING Signaling Adaptor Activity

  • MF: signaling adaptor activity (GO:0035591)
  • Enabled by: STING1 (UniProtKB:Q86WV6)
  • Occurs in: Golgi membrane (GO:0000139)
  • Part of: pattern recognition receptor signaling pathway (GO:0002221)
  • Evidence: Direct assay evidence (ECO:0000314, PMID:23910378)
  • Causal connection: directly positively regulates TBK1 kinase activity

This annotation correctly captures STING's role as a signaling adaptor in the innate immune response pathway.

5. TBK1 Kinase Activity

  • MF: protein serine/threonine kinase activity (GO:0004674)
  • Enabled by: TBK1 (UniProtKB:Q9UHD2)
  • Occurs in: cytoplasm (GO:0005737)
  • Part of: cytoplasmic pattern recognition receptor signaling pathway (GO:0002753)
  • Evidence: Direct assay evidence (ECO:0000314, PMID:14703513)

TBK1 is appropriately annotated as a kinase downstream of STING in the signaling pathway.

Consistency with GO-CAM Best Practices

The model follows best practices for annotating molecular adaptors: 1. Correctly uses the 'protein-macromolecule adaptor activity' term for Vif 2. Appropriately uses 'provides input for' to connect Vif adaptor activity to PTPN6 phosphatase activity 3. Correctly uses 'directly negatively regulates' for the inhibitory effect of PTPN6 on STING 4. Properly annotates the cellular components where these activities occur 5. Documents each activity with relevant PMIDs and evidence codes

Biological Accuracy

The model accurately represents the mechanism described in Wang et al. (2021), which demonstrates that: 1. HIV-1 Vif inhibits type I interferon production 2. FRK phosphorylates Vif's ITIM motif 3. Phosphorylated Vif recruits PTPN6 (SHP-1) 4. PTPN6 dephosphorylates STING at Tyr162 5. This inhibits STING's K63-linked ubiquitination at Lys337 6. This suppresses STING-mediated innate immune responses

The model has effectively captured this mechanism using appropriate GO terms and relations.

Suggestions for Improvement

  1. Complete the signaling cascade: The model could be extended to include IRF3 activation and type I interferon production downstream of TBK1.

  2. Add specific phosphorylation sites: While the model captures the key activities, it could be enhanced by including specific details about the phosphorylation sites (e.g., Vif ITIM phosphorylation by FRK and STING Tyr162 dephosphorylation by PTPN6).

  3. Include ubiquitination: The model could include the K63-linked ubiquitination of STING at Lys337, which is inhibited by PTPN6-mediated dephosphorylation.

  4. Include details on FRK inhibition: The Wang et al. paper mentions that FRK inhibitor D-65495 can block Vif phosphorylation, which could be an interesting regulatory aspect to include.

Conclusion

GO-CAM model gomodel:663d668500000226 accurately represents the mechanism of HIV-1 Vif-mediated inhibition of STING through PTPN6 recruitment. The model is well-structured, follows GO-CAM best practices for annotating molecular adaptors, and is supported by strong experimental evidence. The causal relationships between the activities are appropriately modeled using the correct relations.

This model provides valuable insights into how HIV-1 evades host antiviral immunity through the STING signaling pathway and could be useful for developing therapeutic strategies against HIV-1 infection.