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GO-CAM Model Review: gomodel:62e3212700001890

Basic Model Information

  • Model ID: gomodel:62e3212700001890
  • Title: Regulation of energy homeostasis by OTUD3 (Human)
  • Taxon: Human (NCBITaxon:9606)
  • Status: Production

Model Overview

This GO-CAM model describes the regulatory pathway through which OTUD3 (a deubiquitinase) regulates energy homeostasis in response to nutritional stress. The model shows how OTUD3 is acetylated by CREBBP (CBP), then deubiquitinates and stabilizes the nuclear receptor PPARD, which in turn regulates transcription of genes involved in energy metabolism.

Pathway Flow

The pathway in this model follows this sequence: 1. CREBBP (CBP) acetyltransferase activity acetylates OTUD3 2. Acetylated OTUD3 functions as a deubiquitinase in the nucleus 3. OTUD3 deubiquitinates PPARD, preventing its degradation 4. Stabilized PPARD acts as a DNA-binding transcription factor to regulate genes involved in energy homeostasis

Model Components Review

1. CREBBP Activity (UniProtKB:Q92793)

  • Activity: Peptide-lysine-N-acetyltransferase activity (GO:0061733)
  • Cellular Location: Cytoplasm (GO:0005737)
  • Process: N-terminal peptidyl-lysine acetylation (GO:0018076)
  • Regulation: Directly positively regulates CREBBP's second activity

Assessment: This representation is accurate. CREBBP is known to acetylate various proteins, and according to the primary literature (PMID:35675826), glucose and fatty acids trigger CREBBP to acetylate OTUD3, promoting its nuclear translocation.

2. Secondary CREBBP Activity

  • Activity: Peptide-lysine-N-acetyltransferase activity (GO:0061733)
  • Cellular Location: Cytoplasm (GO:0005737)
  • Process: N-terminal peptidyl-lysine acetylation (GO:0018076)
  • Regulation: Directly positively regulates OTUD3 deubiquitinase activity

Assessment: This is appropriate and represents the same activity of CREBBP when directly regulating OTUD3.

3. OTUD3 Activity (UniProtKB:Q5T2D3)

  • Activity: Cysteine-type deubiquitinase activity (GO:0004843)
  • Cellular Location: Nucleus (GO:0005634)
  • Process: Protein K48-linked deubiquitination (GO:0071108)
  • Regulation: Directly positively regulates PPARD transcription factor activity

Assessment: This is consistent with the evidence. OTUD3 deubiquitinates and stabilizes PPARD in the nucleus, particularly in response to nutritional stress according to PMID:35675826.

4. PPARD Activity (UniProtKB:Q03181)

  • Activity: DNA-binding transcription factor activity (GO:0003700)
  • Cellular Location: Nucleus (GO:0005634)
  • Process: Regulation of transcription by RNA polymerase II (GO:0006357)

Assessment: This representation is accurate. PPARD is indeed a nuclear transcription factor that regulates genes involved in energy metabolism.

Evidence Assessment

The model is primarily supported by evidence from PMID:35675826, which appears to be a 2022 paper describing the role of OTUD3 in regulating metabolism homeostasis in response to nutritional stresses. The evidence is consistently applied across all activities with ECO:0000314 (direct assay evidence used in manual assertion).

QC Issues and Recommendations

Strengths

  1. The model correctly captures the causal relationships in this regulatory pathway
  2. The cellular locations of each activity are accurately represented
  3. The evidence is consistently sourced and applied throughout the model
  4. The biological processes associated with each function are appropriate

Potential Improvements

  1. Target Gene Specification: According to the DNA-binding transcription factor annotation guidelines, each transcriptional target of PPARD should be captured as a separate activity unit with a "has input" relationship. The current model doesn't specify which genes PPARD regulates.

  2. Molecular Context For OTUD3: The model would benefit from adding that OTUD3 is acetylated (the result of CREBBP action) as context for its deubiquitinase activity. This would help capture that acetylation promotes OTUD3's nuclear localization.

  3. Energy Homeostasis Process: While the title mentions energy homeostasis (GO:0097009), this process isn't explicitly connected to any of the activities in the model. It would be valuable to connect the PPARD transcription factor activity to this process using a "part of" relation.

  4. Nutritional Stress Response: The model could be improved by indicating that this pathway is activated in response to nutritional stresses (e.g., glucose and fatty acids), which is a key aspect of the study referenced.

  5. Ubiquitination Status: The model correctly notes that OTUD3 performs "protein K48-linked deubiquitination" on PPARD, but it would be informative to note that this prevents proteasomal degradation of PPARD, explicitly capturing the stabilization aspect.

Conclusion

The GO-CAM model (gomodel:62e3212700001890) successfully represents the regulatory pathway through which OTUD3 influences energy homeostasis by deubiquitinating and stabilizing PPARD following acetylation by CREBBP. The model is supported by appropriate evidence and follows most GO-CAM curation practices.

The main recommendations for improvement involve adding more specific information about PPARD's transcriptional targets, explicitly connecting the pathway to energy homeostasis, and providing more context about the nutritional stress response. These changes would enhance the biological completeness of the model while maintaining its current strengths in representing the causal flow of the pathway.