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654d809000000248 Regulation of aggrephagy via phosphorylation of SQSTM1 by CK2 Human

Now I'll review the GO-CAM model with ID 654d809000000248, titled "Regulation of aggrephagy via phosphorylation of SQSTM1 by CK2 (Human)."

GO-CAM Model Review: gomodel:654d809000000248

Model Overview

This model describes the regulation of aggrephagy (selective autophagy of protein aggregates) through the phosphorylation of SQSTM1 (Sequestosome-1, also known as p62) by the protein kinase CK2 (Casein Kinase 2) in humans. The model shows how CK2 phosphorylation of SQSTM1 affects its function in recognizing and targeting ubiquitinated proteins for autophagic degradation.

Entities and Activities in the Model

  1. CSNK2A1/CK2 (UniProtKB:P68400)
  2. Molecular function: Protein serine/threonine kinase activity (GO:0004674)
  3. Biological process: Positive regulation of aggrephagy (GO:1905337)

  4. Causal association: Directly positively regulates (RO:0002629) SQSTM1's ubiquitin-modified protein reader activity

  5. SQSTM1/p62 (UniProtKB:Q13501)

  6. Has three activities in the model:

    1. Ubiquitin-modified protein reader activity (GO:0140036)

      • Occurs in: Cytosol (GO:0005829)
      • Part of: Aggrephagy (GO:0035973)
      • Directly positively regulates (RO:0002629) SQSTM1's molecular condensate scaffold activity

    2. Molecular condensate scaffold activity (GO:0140693)

      • Occurs in: Intracellular membraneless organelle (GO:0043232)
      • Part of: Membraneless organelle assembly (GO:0140694)
      • Directly positively regulates (RO:0002629) SQSTM1's protein-macromolecule adaptor activity

    3. Protein-macromolecule adaptor activity (GO:0030674)

      • Occurs in: Autophagosome (GO:0005776)
      • Part of: Protein targeting to vacuole involved in autophagy (GO:0071211)

Evidence and References

The model is supported by multiple scientific publications, including: - PMID:29507397 (Sun et al., 2018) - PMID:29343546 (Zaffagnini et al., 2018) - PMID:31857589 (You et al., 2019) - PMID:22017874 (Matsumoto et al., 2011) - PMID:37802024 (Huang et al., 2023) - PMID:8650207 (Joung et al., 1996)

Review Assessment

Strengths of the Model:

  1. Appropriate Causal Flow: The model correctly represents the sequential causal flow from CK2 kinase activity → SQSTM1 ubiquitin-modified protein reader activity → SQSTM1 molecular condensate scaffold activity → SQSTM1 adaptor activity.

  2. Well-Supported by Evidence: Each activity and causal link is supported by peer-reviewed publications.

  3. Correct Biochemical Knowledge: The model accurately captures the known role of CK2 phosphorylation of SQSTM1 at Ser403, which enhances SQSTM1's ability to bind ubiquitinated proteins.

  4. Proper Cellular Localization: The model correctly places activities in their appropriate cellular compartments.

  5. Clear Molecular Mechanism: The model shows a clear pathway from kinase activity to the functional outcomes in autophagy.

Suggestions for Improvement:

  1. Phosphorylation Site Specification: Consider explicitly noting the phosphorylation site (Ser403) on SQSTM1 that's targeted by CK2. This would make the specific molecular event clearer.

  2. Additional Important Interactions: The model could be expanded to include MAP1LC3A/LC3 interaction with SQSTM1, which is mentioned in the UniProtKB entry and is critical for the recruitment of autophagic machinery.

  3. Temporal Relationship: Consider clarifying the temporal sequence of events, as SQSTM1 first forms bodies with ubiquitinated proteins (phase separation) before being recruited to autophagosomes.

Compliance with GO-CAM Best Practices:

The model follows GO-CAM best practices by: - Using appropriate molecular function terms for each protein - Properly connecting activities with causal relationships - Including cellular locations for activities - Linking activities to their broader biological processes

According to the "How to annotate complexes in GO-CAM" document, this model appropriately represents the activities of individual proteins rather than complexes, as the specific activities of CK2 and SQSTM1 are well-defined in the literature.

Conclusion:

This GO-CAM model (gomodel:654d809000000248) is a well-constructed representation of the role of CK2-mediated phosphorylation in regulating SQSTM1's function during aggrephagy. It accurately captures the molecular events and causal relationships involved in this process. The model is scientifically sound and follows GO-CAM best practices.

The biological content aligns with current literature on SQSTM1 regulation. CK2 (CSNK2A1) phosphorylates SQSTM1 at Ser403, which enhances its binding to ubiquitinated proteins. This facilitates SQSTM1's phase separation and formation of protein aggregates (p62 bodies), which are subsequently targeted to autophagosomes for degradation.

This model is parsimonious and focused on the key molecular events, making it easy to understand while accurately representing the biological pathway.