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Based on my review of the GO-CAM model and the relevant scientific literature, I'll now provide a comprehensive review of gomodel:66c7d41500000427 "Zika virus NS5 inhibition of STAT2 signaling via ZSWIM8 (Human)".

GO-CAM Model Review: gomodel:66c7d41500000427

Model Summary

Title: Zika virus NS5 inhibition of STAT2 signaling via ZSWIM8 (Human)
Taxon: NCBITaxon:9606 (Human)
Status: Production
ID: gomodel:66c7d41500000427

Model Overview

This GO-CAM model represents the mechanism by which Zika virus NS5 protein inhibits interferon signaling by targeting the STAT2 protein for degradation via the ZSWIM8-containing Cullin-RING E3 ubiquitin ligase complex. The model illustrates a key viral immune evasion strategy that helps Zika virus overcome host antiviral defenses.

Biological Content Evaluation

The model accurately represents a well-documented mechanism of viral immune evasion based on current literature. The key molecular players include:

  1. ZSWIM8 (UniProtKB:A7E2V4) - Functions as a ubiquitin-like ligase-substrate adaptor
  2. Zika virus NS5 (UniProtKB:Q32ZE1) - Acts as a protein-macromolecule adaptor
  3. CUL3 (UniProtKB:Q13618) - Functions as ubiquitin ligase complex scaffold
  4. STAT2 (UniProtKB:P52630) - The target transcription factor that gets degraded

Activity Flow Assessment

The model correctly captures the causal flow of activities:

  1. Zika virus NS5 (GO:0030674 - protein-macromolecule adaptor activity) provides input for the ZSWIM8 activity. This is supported by PMID:39145933, which shows that NS5 acts as a scaffold protein connecting the ZSWIM8-CUL3 E3 ligase complex to STAT2.

  2. ZSWIM8 (GO:1990756 - ubiquitin-like ligase-substrate adaptor activity) negatively regulates, through direct negative regulation (RO:0002409), the STAT2 activity. This is well supported by PMID:33184234.

  3. CUL3 (GO:0160072 - ubiquitin ligase complex scaffold activity) directly positively regulates (RO:0002629) the activity of ZSWIM8. This is supported by PMID:23453970.

  4. The degradation of STAT2 prevents its DNA-binding transcription factor activity (GO:0003700), which would normally function in the type I interferon-mediated signaling pathway (GO:0060337).

Evidence Evaluation

The model is well-supported by multiple recent scientific publications:

  • PMID:33184234 (2020) - Identifies ZSWIM8 as a key component in the ubiquitin ligase complex
  • PMID:39145933 (2023) - Specifically demonstrates how Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2
  • PMID:23453970 (2013) - Establishes the role of CUL3 in the ubiquitin ligase complex
  • PMID:31127039 (2019) - Documents STAT2's role as a DNA-binding transcription factor
  • PMID:23391734 (2013) - Describes the function of STAT2 in type I interferon signaling pathway

All evidence types are appropriate, primarily using ECO:0000314 (direct assay evidence used in manual assertion).

Cellular Location Accuracy

The model correctly represents the cellular locations:

  • ZSWIM8 activity occurs in the cytosol (GO:0005829)
  • Zika virus NS5 is correctly shown in the host cell cytoplasm (GO:0030430)
  • CUL3 is shown in the cytoplasm (GO:0005737)
  • STAT2 is shown in the nucleus (GO:0005634), which is appropriate since that's where it would function as a transcription factor (when not degraded)

Alignment with GO-CAM Best Practices

The model follows GO-CAM best practices:

  1. Appropriate GO terms: The molecular functions, cellular components, and biological processes are all appropriately selected.

  2. Correct causal relationships: The model uses appropriate causal predicates:

  3. RO:0002413 (provides input for) for NS5 to ZSWIM8
  4. RO:0002409 (negatively regulated by) for ZSWIM8 to STAT2

  5. RO:0002629 (directly positively regulates) for CUL3 to ZSWIM8

  6. Proper evidence documentation: Each association includes evidence codes, reference citations, and contributor information.

  7. Species specificity: The model clearly indicates it represents the human system.

Parsimony and Clarity

The model is parsimonious and clear: - It focuses on the core mechanism of STAT2 degradation without unnecessary complexity - The causal flow is logical and easy to follow - It correctly represents the roles of all four key proteins in the process - It accurately captures the immune evasion strategy of Zika virus

Recommendations

The model is scientifically accurate and well-constructed. Some minor potential enhancements could include:

  1. Expanding upstream regulators: Consider adding information on what activates the CUL3 complex in this context (if known).

  2. Downstream effects: The model could potentially be expanded to show the specific genes whose expression is affected by the loss of STAT2 activity.

  3. Temporal aspects: If temporal data is available about when during infection this mechanism is most active, this could be added as annotation.

Overall Assessment

This GO-CAM model accurately represents the current scientific understanding of how Zika virus NS5 inhibits STAT2 signaling via ZSWIM8. It is well-supported by recent literature, follows GO-CAM best practices, and clearly illustrates an important viral immune evasion mechanism. The model is biologically accurate, properly connects activities in a meaningful causal flow, and is built with appropriate evidence.

The model makes a valuable contribution to understanding how Zika virus evades the host immune response and could be useful for researchers studying viral pathogenesis and host-pathogen interactions.