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617b481400000559 KAT5 regulation of lipid droplet disassembly Human

Based on my review of the GO-CAM model (gomodel:617b481400000559) titled "KAT5 regulation of lipid droplet disassembly (Human)" and the relevant information I've gathered, here's my detailed assessment:

Model Structure Review

This model represents a cellular pathway where KAT5 (histone acetyltransferase) regulates lipid droplet disassembly in response to glucose starvation in human cells. The model includes the following key activities and relationships:

  1. PRKAA1 (Q13131, AMPK alpha-1) and PRKAA2 (P54646, AMPK alpha-2) both perform protein serine/threonine kinase activity (GO:0004674), as part of cellular response to glucose starvation (GO:0042149), and both positively regulate KAT5 transcription activity and phosphorylate CHKA.

  2. KAT5 (Q92993) performs peptide-lysine-N-acetyltransferase activity (GO:0061733), as part of cellular response to glucose starvation (GO:0042149), and negatively regulates CHKA homodimerization while positively regulating CHKA protein binding.

  3. CHKA (P35790-1, isoform 1) has:

  4. Protein homodimerization activity (GO:0042803) in the cytosol, part of phosphatidylcholine biosynthetic process
  5. Protein binding activity (GO:0005515) in lipid droplets, in response to glucose starvation
  6. Choline kinase activity (GO:0004103) in the cytosol
  7. Ethanolamine kinase activity (GO:0004305) in the cytosol
  8. Protein tyrosine kinase activity (GO:0004713) in lipid droplets, part of lipid droplet disassembly

Scientific Content Assessment

The model accurately captures the findings reported in the primary article (PMID:34077757), specifically:

  1. Mechanism of regulation: The model correctly shows that AMPK (PRKAA1 and PRKAA2) phosphorylates CHKA at Ser-279 upon glucose deprivation, which promotes its localization to lipid droplets.

  2. KAT5-mediated acetylation: KAT5 subsequently acetylates CHKA at Lys-247, promoting dissociation of the CHKA homodimer into monomers.

  3. Functional shift: The model accurately depicts that acetylated monomeric CHKA is converted into a protein tyrosine kinase that phosphorylates lipid droplet structural proteins (though I note the model doesn't explicitly show the downstream targets PLIN2 and PLIN3).

  4. Biological outcome: The model appropriately shows the culmination of this pathway as lipid droplet disassembly (GO:1905691).

Annotation Quality Review

  1. Correct use of GO terms: The molecular functions, biological processes, and cellular components are appropriately assigned.

  2. Proper use of causal associations:

  3. RO:0002629 (directly positively regulates) and RO:0002630 (directly negatively regulates) are used correctly to show direct regulation.

  4. RO:0002304 (causally upstream of, positive effect) is correctly used for the indirect positive regulation.

  5. Evidence annotations: All activities are appropriately supported with ECO:0000314 (direct assay evidence used in manual assertion) and refer to the primary paper PMID:34077757.

  6. Localization information: The model correctly includes cellular localization information for CHKA, showing its presence in both cytosol and lipid droplets.

GO-CAM Best Practices Compliance

The model follows GO-CAM best practices for:

  1. Activity flow: The activities are connected in a way that is consistent with the biological pathway.

  2. Complex representation: The model correctly handles the CHKA homodimer, following the guidelines in "How to annotate complexes in GO-CAM" by properly showing the homodimerization activity.

  3. Protein modification effects: The model appropriately captures how post-translational modifications (phosphorylation followed by acetylation) affect protein function.

Suggestions for Improvement

While the model is scientifically accurate and well-constructed, I'd suggest a few minor improvements:

  1. Complete the pathway: Consider adding the specific lipid droplet proteins (PLIN2 and PLIN3) that are phosphorylated by monomeric CHKA's tyrosine kinase activity. This would complete the mechanistic picture of how lipid droplet disassembly occurs.

  2. Clearer activity visualization: The model might benefit from a clearer visual representation of the transition from CHKA homodimer to monomer following acetylation.

  3. Additional contextual information: Consider adding information about adenylate charge sensing (a key function of AMPK) as part of the glucose starvation response.

Overall Assessment

This GO-CAM model (gomodel:617b481400000559) is a high-quality representation of the KAT5-mediated regulation of lipid droplet disassembly pathway. It accurately captures the scientific content from the literature, follows GO-CAM best practices, and provides a clear depiction of the activity flow in the pathway. The model is parsimonious and presents the information in a way that would be understandable to a human curator.

The model effectively represents a novel and important regulatory mechanism where a metabolic enzyme (CHKA) is converted to a protein kinase through post-translational modifications, leading to lipid droplet disassembly during glucose starvation.