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Now I'll review the GO-CAM model with ID 60ad85f700000612 based on all the information gathered. I'll structure my review to check for consistency with GO-CAM best practices, biological accuracy, and proper molecular function representation.

Review of GO-CAM model: gomodel:60ad85f700000612 "TRIM47-activity-on-ILF3"

Overview

This GO-CAM describes a causal pathway involving four proteins: 1. HAVCR2/TIM-3 (UniProtKB:Q8TDQ0) 2. TRIM47 (UniProtKB:Q96LD4-1) 3. ILF3/NF90 (UniProtKB:Q12906) 4. EIF2AK2/PKR (UniProtKB:P19525)

The model represents a molecular pathway where: 1. HAVCR2/TIM-3 protein binding directly positively regulates 2. TRIM47's E3 ubiquitin ligase activity, which directly negatively regulates 3. ILF3/NF90's virus receptor activity, which is also regulated by 4. EIF2AK2/PKR's kinase activity that directly positively regulates ILF3/NF90

Consistency with GO-CAM Best Practices

Representation of Protein Complex Activities

According to the "How to annotate complexes in GO-CAM" document, the model correctly follows the practice of representing the individual protein activities when the specific activity-carrying subunits are known. The model doesn't include a complex term but instead shows the individual proteins and their activities, which is appropriate when the specific roles of individual proteins are being modeled.

Causal Associations

The model uses appropriate causal predicates: - RO:0002629 (directly positively regulates) between HAVCR2 and TRIM47 - RO:0002630 (directly negatively regulates) between TRIM47 and ILF3 - RO:0002629 (directly positively regulates) between EIF2AK2 and ILF3

These are appropriate predicates for describing direct regulatory relationships between molecular activities.

Evidence Support

All molecular functions and causal associations are supported by experimental evidence: - ECO:0000314 (direct assay evidence used in manual assertion) - From PMIDs: 34110282 and 21123651

The use of direct experimental evidence is appropriate and well-documented.

Biological Content Review

The model is based primarily on findings from two papers:

  1. PMID:34110282 (Dou et al., 2021): "Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity"
  2. PMID:21123651 (Harashima et al., 2010): "Phosphorylation of the NFAR proteins by the dsRNA-dependent protein kinase PKR constitutes a novel mechanism of translational regulation and cellular defense"

The model accurately represents the key findings from these papers:

  1. TIM-3 (HAVCR2) interacts with and promotes TRIM47 E3 ubiquitin ligase activity
  2. TRIM47 ubiquitinates ILF3/NF90 at Lys297, leading to its degradation
  3. This degradation inhibits ILF3's antiviral function
  4. PKR (EIF2AK2) phosphorylates ILF3/NF90, which activates its antiviral function

The GO-CAM accurately captures the opposing regulatory effects of TIM-3/TRIM47 (negative) versus PKR (positive) on ILF3's function.

Biological Issues

  1. Annotation of ILF3 activity: ILF3 is annotated with GO:0001618 (virus receptor activity). This seems questionable as the primary function of ILF3 in the context described is as an antiviral protein that recognizes viral RNAs. The papers describe it as an RNA-binding protein involved in antiviral responses. A more appropriate term might be GO:0003723 (RNA binding) or GO:0003725 (double-stranded RNA binding) since that's its activity that mediates antiviral response.

  2. EIF2AK2/PKR occurs_in GO:0005737 (cytoplasm): While this is correctly annotated as per the literature (PKR is primarily cytoplasmic), the model would be more complete if it noted that according to Harashima et al., PKR's phosphorylation of ILF3 causes it to be retained in the cytoplasm where it can bind viral RNAs.

Technical Aspects

  1. Evidential Support: All activities are supported by appropriate experimental evidence from the literature, which is properly cited.

  2. Connectivity: The model shows good connectivity between activities, representing a coherent causal pathway.

  3. Enables_by annotations: Each activity is properly annotated with the protein that enables it.

Recommendations for Improvement

  1. Re-evaluate the molecular function assigned to ILF3/NF90: Consider changing from "virus receptor activity" (GO:0001618) to a more specific function like "double-stranded RNA binding" (GO:0003725), which better reflects its antiviral mechanism described in the papers.

  2. Add spatial context: Consider adding occurs_in annotations for ILF3, noting that phosphorylated ILF3 is retained in the cytoplasm according to Harashima et al.

  3. Consider adding more detailed information about the ubiquitination site: The model could note that TRIM47 specifically targets Lys297 of ILF3 for ubiquitination as mentioned in the Dou et al. paper.

  4. Consider expanding the model to include downstream effects: The papers discuss how this pathway affects viral replication and innate immune response, which could be included to make the model more complete.

Conclusion

This GO-CAM model (gomodel:60ad85f700000612) provides a well-structured representation of the regulatory relationship between HAVCR2, TRIM47, ILF3, and EIF2AK2 in the context of antiviral innate immunity. The model follows GO-CAM best practices and is supported by direct experimental evidence from the literature.

The main issue is the molecular function assigned to ILF3, which should be reconsidered to better reflect its RNA-binding role in antiviral defense rather than as a virus receptor. With this adjustment and some additional contextual information, the model would provide an even more accurate representation of the biological pathway.