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Based on all the information I've gathered, let me now provide a detailed review of the GO-CAM model "gomodel:635b1e3e00001811" titled "The NLRP3 inflammasome (Human)":

Review of GO-CAM Model: The NLRP3 inflammasome (Human)

Summary

This GO-CAM model (ID: gomodel:635b1e3e00001811) represents the NLRP3 inflammasome pathway in humans, depicting how this crucial innate immune complex assembles and functions to trigger pyroptosis and cytokine secretion. The model shows the activities of several key proteins including NLRP3, CASP1, GSDMD, and the resulting mature cytokines IL1B and IL18.

Strengths of the Model

  1. Comprehensive pathway representation: The model effectively captures the key components and activities in the NLRP3 inflammasome pathway, from sensor activation to cytokine secretion.

  2. Correct use of causal relationships: The model uses appropriate causal relationships (mostly RO:0002629 "directly positively regulates") between activities.

  3. Well-supported evidence: Each activity and relationship has appropriate evidence codes (ECO:0000314 - direct assay evidence used in manual assertion) with supporting literature references.

  4. Appropriate molecular functions: The molecular functions assigned to each protein are appropriate based on their known roles (e.g., NLRP3 with sensing and adaptor activity, GSDMD with channel activity).

  5. Logical flow of activities: The model shows a clear progression from NLRP3 sensing to inflammasome assembly, caspase-1 activation, gasdermin D cleavage, and finally cytokine release.

Areas for Improvement

  1. Cellular component annotations: While most components have appropriate cellular locations, some refinements could be made:

  2. NLRP3 (UniProtKB:Q96P20) is shown in multiple locations (GO:0005815 microtubule organizing center, GO:0016020 membrane). While this is consistent with the literature, indicating specific membrane compartments like "Golgi apparatus membrane" (based on UniProt data) would be more precise.

  3. Missing environmental triggers: The model doesn't explicitly represent the stimuli that activate NLRP3 (e.g., PAMPs, DAMPs, ATP, nigericin). Including these would provide a more complete picture of inflammasome activation.

  4. Complexes representation: According to the "How to annotate complexes in GO-CAM" guideline, when the subunit carrying an activity is known, individual proteins should be represented rather than using a complex ID. The model follows this correctly by showing individual components, but it could be useful to explicitly show the complex formation step.

  5. NEK7 regulation of NLRP3: The model includes NEK7's molecular function activator activity (GO:0140677) acting on NLRP3, which is accurate according to the literature. However, the mechanism by which NEK7 licenses NLRP3 activation could be more explicitly shown, as it's a critical regulatory step.

  6. PYCARD/ASC representation: While NLRP3 and CASP1 are represented, the adaptor protein PYCARD/ASC (which bridges NLRP3 and CASP1) is not explicitly included in the model. Adding PYCARD would make the model more complete.

  7. Upstream signaling events: The model could include the "priming" step of NLRP3 inflammasome activation, which involves NF-κB-mediated transcriptional upregulation of NLRP3 and pro-IL1B.

Specific Comments on Activities and Relationships

  1. NLRP3 activities (UniProtKB:Q96P20):
  2. Correctly shown with multiple molecular functions including molecular sensor activity (GO:0140299), signaling adaptor activity (GO:0035591), and phospholipid binding activities (GO:0070273).
  3. The model correctly represents the localization to microtubule organizing center and membrane.

  4. The activities are appropriately connected to show the sequential activation of NLRP3.

  5. CASP1 activities (UniProtKB:P29466):

  6. Appropriately shown with cysteine-type endopeptidase activity (GO:0004197).

  7. The causal relationships showing CASP1 cleaving GSDMD and pro-cytokines are accurate.

  8. GSDMD activities (UniProtKB:P57764):

  9. Correctly represented with phospholipid binding activities (GO:0070273, GO:0005546) and wide pore channel activity (GO:0022829).

  10. The progression from binding phospholipids to forming pores that allow cytokine release is well-represented.

  11. Cytokine activities (IL1B and IL18):

  12. Both are appropriately shown with cytokine activity (GO:0005125) in the extracellular space.

  13. The model correctly shows these as the terminal outputs of the pathway.

  14. NEK7 regulation:

  15. The molecular function activator activity (GO:0140677) of NEK7 directly regulating NLRP3 is well-supported by recent literature.

Consistency with Literature

The model is consistent with current understanding of NLRP3 inflammasome biology, including:

  1. The role of NLRP3 as a sensor for various stimuli
  2. The requirement for NEK7 as a licensing factor for NLRP3 activation
  3. The cleavage of GSDMD by CASP1 to form membrane pores
  4. The maturation and secretion of IL1B and IL18 through these pores

The model reflects findings from recent publications (e.g., PMID:35254907, PMID:35114687, PMID:36227980) cited in the evidence.

Suggestions for Enhancement

  1. Add PYCARD/ASC: Include PYCARD (UniProtKB:Q9ULZ3) and its pyrin domain-mediated interactions with NLRP3, which is essential for inflammasome assembly.

  2. Represent oligomerization states: The model could explicitly show the oligomerization of NLRP3 and PYCARD/ASC, which is crucial for inflammasome function.

  3. Include priming step: Add the LPS/NF-κB-mediated priming events that upregulate NLRP3 and pro-IL1B expression.

  4. Show post-translational modifications: Include key PTMs like phosphorylation, ubiquitination, and palmitoylation that regulate NLRP3 activity.

  5. Refine membrane locations: Specify the exact membrane compartments where NLRP3 and GSDMD operate (e.g., Golgi, plasma membrane).

Conclusion

Overall, this is a well-constructed GO-CAM model that accurately represents the current understanding of NLRP3 inflammasome biology. The model effectively captures the key molecular activities and causal relationships in the pathway. With a few enhancements to include additional components and regulatory events, it could provide an even more comprehensive representation of this important innate immune pathway.