Skip to content

Let me review the GO-CAM model 61e0e55600001659 based on the information I've gathered:

Review of GO-CAM Model: gomodel:61e0e55600001659

Model Overview

Title: Granzyme-mediated (GZMB) activation of pyroptosis (GSDME) (Human)
ID: gomodel:61e0e55600001659
Taxon: Human (NCBITaxon:9606)
Status: Production

Biological Process Represented

This model describes the molecular pathway for granzyme B (GZMB)-mediated activation of gasdermin E (GSDME) leading to pyroptotic cell death in humans. This process is particularly important for the immune system's ability to eliminate cancer cells and infected cells.

Model Structure and Components

The model includes four key molecular activities:

  1. NINJ1 (Ninjurin-1, UniProtKB:Q92982): Functions in membrane destabilizing activity (GO:0140912) at the plasma membrane (GO:0005886) as part of the pyroptotic cell death process (GO:0141201).

  2. GSDME (Gasdermin E, UniProtKB:O60443): Functions with wide pore channel activity (GO:0022829) as part of pyroptotic cell death (GO:0141201).

  3. PRF1 (Perforin-1, UniProtKB:P14222): Functions with wide pore channel activity (GO:0022829) at the plasma membrane (GO:0005886) as part of protein transmembrane transport (GO:0071806).

  4. GZMB (Granzyme B, UniProtKB:P10144): Functions with serine-type endopeptidase activity (GO:0004252) in the cytoplasm (GO:0005737) as part of protein maturation (GO:0051604).

Causal Relationships

The model includes causal relationships showing the flow of activity:

  1. PRF1 positively regulates GZMB (RO:0002304 - causally upstream of, positive effect).
  2. GZMB directly positively regulates GSDME (RO:0002629 - directly positively regulates).
  3. GSDME directly positively regulates NINJ1 (RO:0002629 - directly positively regulates).

Evidence Assessment

The model is well supported by substantial experimental evidence, with each activity and causal relationship documented with experimental evidence (ECO:0000314 - direct assay evidence) and recent publications:

  • Activities of NINJ1 are supported by 2024 publications (PMID:38614101, PMID:37198476, PMID:37196676, PMID:36468682, PMID:33472215)
  • Activities of GSDME are supported by 2022 publications (PMID:32188940)
  • Activities of PRF1 are supported by 2010 publications (PMID:20038786)
  • Activities of GZMB are supported by 2020 and 2019 publications (PMID:32188940, PMID:31953257)

Biological Accuracy

The model accurately captures the current understanding of GZMB-mediated pyroptosis through GSDME:

  1. Perforin (PRF1) forms pores in target cell membranes and facilitates the entry of granzyme B (GZMB).
  2. Granzyme B cleaves gasdermin E (GSDME) at the D270 site, releasing the N-terminal pore-forming domain.
  3. GSDME forms pores in the cell membrane, leading to membrane destabilization.
  4. NINJ1 (Ninjurin-1) acts downstream of GSDME to execute plasma membrane rupture, leading to pyroptotic cell death.

This mechanism is consistent with recent discoveries that NINJ1 is a key executioner of plasma membrane rupture during various forms of lytic cell death, including pyroptosis (as described in PMID:37198476 and PMID:38614101).

Adherence to GO-CAM Best Practices

The model follows GO-CAM best practices:

  1. Appropriate molecular functions: Each protein is annotated with a valid molecular function (e.g., GZMB with serine-type endopeptidase activity).
  2. Proper cellular component annotations: Components are placed in the correct cellular locations (e.g., PRF1 and NINJ1 at plasma membrane, GZMB in cytoplasm).
  3. Logical causal connections: The causal flow from PRF1 → GZMB → GSDME → NINJ1 reflects the biological sequence accurately.
  4. Evidence citations: All annotations are supported by appropriate experimental evidence codes and literature references.
  5. Appropriate use of relation types: The model uses the correct causal relationships (RO:0002304 and RO:0002629) to show the directionality and type of influence.

Suggestions for Improvement

While the model is generally well-constructed, I would suggest a few minor improvements:

  1. Additional contextual information: The model could benefit from explicitly noting that this pathway is particularly relevant in the context of cytotoxic lymphocyte-mediated killing of tumor cells or infected cells, as highlighted in PMID:32188940.

  2. Process expansion: The biological outcome of NINJ1 activity could be more explicitly modeled. NINJ1 leads to plasma membrane rupture, which is the defining event of pyroptotic cell death that releases DAMPs (damage-associated molecular patterns), but this final step and its consequences aren't fully represented.

  3. Potential refinements to causal relationships: Based on PMID:38614101, NINJ1 appears to be activated by GSDME-mediated pores, so the causal relationship from GSDME to NINJ1 is correctly captured. However, from PMID:37198476, it appears that NINJ1 has a more complex role in membrane destabilization through formation of filamentous structures.

Conclusion

GO-CAM model gomodel:61e0e55600001659 is a high-quality representation of the GZMB-mediated activation of pyroptosis through GSDME and NINJ1. It accurately captures current knowledge of this pathway, is well-supported by recent experimental evidence, and adheres to GO-CAM best practices. The model successfully integrates recent discoveries about NINJ1's role as the terminal executioner of cell membrane rupture during pyroptotic cell death. This model provides valuable insight into the mechanism by which cytotoxic lymphocytes can induce inflammatory cell death in target cells.