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635b1e3e00002004 Activation of the NLRP3 inflammasome by MAPK8 JNK1 and BRCC3 Human

Let me now provide a comprehensive review of the GO-CAM model "gomodel:635b1e3e00002004" - Activation of the NLRP3 inflammasome by MAPK8/JNK1 and BRCC3.

GO-CAM Model Review - "Activation of the NLRP3 inflammasome by MAPK8/JNK1 and BRCC3"

Model Overview

  • Title: Activation of the NLRP3 inflammasome by MAPK8/JNK1 and BRCC3 (Human)
  • ID: gomodel:635b1e3e00002004
  • Taxon: Human (NCBITaxon:9606)
  • Status: Production
  • Comment: "Automated change 2023-03-16: RO:0002213 replaced by RO:0002629"

Model Structure and Key Components

The model focuses on the activation pathway of the NLRP3 inflammasome, involving primarily three key proteins: 1. NLRP3 (UniProtKB:Q96P20) - The NACHT, LRR and PYD domains-containing protein 3 2. MAPK8/JNK1 (UniProtKB:P45983) - Mitogen-activated protein kinase 8 3. BRCC3 (UniProtKB:P46736) - Lys-63-specific deubiquitinase BRCC36

Biological Representation Accuracy

The model accurately represents the current understanding of NLRP3 inflammasome activation as supported by the literature:

  1. NLRP3 Signaling Adaptor Activity (GO:0035591):
  2. Correctly annotated in membrane (GO:0016020) and microtubule organizing center (GO:0005815)
  3. Supported by evidence from PMID:35254907 and PMID:35114687

  4. This is consistent with findings from PMID:30487600 showing NLRP3 localizes to different subcellular compartments during activation

  5. MAPK8/JNK1 Phosphorylation of NLRP3:

  6. Correctly represents protein serine/threonine kinase activity (GO:0004674)
  7. The causal association (RO:0002629 "directly positively regulates") of MAPK8 to BRCC3 deubiquitinase

  8. Based on PMID:28943315 which identified that JNK1-mediated phosphorylation of NLRP3 is essential for inflammasome activation

  9. BRCC3 Deubiquitinase Activity (GO:0061578):

  10. Appropriately shows K63-linked deubiquitinase activity
  11. Connected to NLRP3 activation via "directly positively regulates" relation (RO:0002629)

  12. Supported by PMID:28943315 which demonstrated BRCC3 removes K63-linked ubiquitin from NLRP3

  13. NLRP3 Phosphatidylinositol-4-phosphate Binding (GO:0070273):

  14. Correctly located in membrane (GO:0016020)
  15. Evidence from PMID:30487600 which showed that NLRP3 recruitment to dispersed trans-Golgi network (dTGN) through PI4P binding is essential for inflammasome activation

Pathway Flow Accuracy

The causal relationships in the model accurately depict the sequential activation process:

  1. MAPK8/JNK1 phosphorylates NLRP3 (priming step)
  2. BRCC3 deubiquitinates NLRP3 (removal of K63-linked ubiquitin)
  3. NLRP3 membrane localization through phosphatidylinositol-4-phosphate binding
  4. NLRP3 signaling adaptor activity in NLRP3 inflammasome complex assembly

This sequence aligns with the literature findings that NLRP3 activation involves a two-step process: priming (phosphorylation) and activation (deubiquitination), followed by membrane recruitment and complex formation.

Evidence Standards

The model uses appropriate evidence codes: - ECO:0000314 (direct assay evidence used in manual assertion) for all annotations - Each evidence is backed by peer-reviewed publications (PMID:28943315, PMID:30487600, PMID:35114687, PMID:35254907)

Annotation of Complexes

The model follows GO-CAM best practices for complex annotation as outlined in the "How to annotate complexes in GO-CAM" document:

  • Individual proteins (NLRP3, MAPK8, BRCC3) are annotated with their specific molecular functions
  • NLRP3 is correctly annotated as part of the NLRP3 inflammasome complex assembly (GO:0044546)
  • The causal relationships between functions are appropriately represented

Areas for Potential Improvement

While the model is overall accurate and well-evidenced, there are a few areas that could be enhanced:

  1. Additional NLRP3 Regulatory Mechanisms:

  2. The model focuses on phosphorylation and deubiquitination but could include other regulatory mechanisms like NEK7 interaction, which is mentioned in the literature (PMID:35254907)

  3. Downstream Effects:

  4. The model could be extended to include downstream effects of NLRP3 inflammasome activation, such as caspase-1 activation and IL-1β processing

  5. Alternative Cellular Locations:

  6. While the model correctly represents membrane and MTOC localization, it could also include ER and mitochondrial associations mentioned in some literature

Conclusion

The GO-CAM model "gomodel:635b1e3e00002004" accurately represents the NLRP3 inflammasome activation pathway mediated by MAPK8/JNK1 phosphorylation and BRCC3 deubiquitination. The model is well-supported by scientific evidence and follows GO-CAM best practices for annotation.

The representation of protein functions, subcellular locations, and causal relationships accurately reflects our current understanding of NLRP3 inflammasome biology. The model effectively captures the key regulatory steps in NLRP3 activation, particularly the roles of phosphorylation and deubiquitination in promoting inflammasome assembly.

This model provides a valuable resource for researchers studying inflammasome biology and could be further enhanced by adding additional regulatory mechanisms and downstream effects of NLRP3 activation.