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6348a65d00000594 Granzyme mediated GZMA activation of pyroptosis GSDMB isoform 4 Human

Now that I've gathered all the necessary information, let me review the GO-CAM model gomodel:6348a65d00000594.

GO-CAM Model Review: Granzyme-mediated (GZMA) activation of pyroptosis (GSDMB isoform 4) (Human)

Model Overview

This model (gomodel:6348a65d00000594) represents the mechanism by which granzyme A (GZMA) from cytotoxic lymphocytes triggers pyroptosis in target cells through cleavage of gasdermin-B (GSDMB) isoform 4 in humans. The model shows a detailed molecular pathway with four main activities connected in a causal chain.

Evaluation of Biological Content

Key Proteins and Their Functions:

  1. PRF1 (Perforin) (UniProtKB:P14222)
  2. Correctly annotated with wide pore channel activity (GO:0022829)
  3. Correctly shown as occurring in the plasma membrane (GO:0005886)
  4. Part of protein transmembrane transport (GO:0071806)

  5. Accurately positioned as the upstream activity enabling GZMA to enter target cells

  6. GZMA (Granzyme A) (UniProtKB:P12544)

  7. Correctly annotated with serine-type endopeptidase activity (GO:0004252)
  8. Accurately shown as occurring in the cytoplasm (GO:0005737), consistent with its delivery into target cells
  9. Part of protein maturation (GO:0051604)

  10. Correctly positioned as cleaving GSDMB

  11. GSDMB isoform 4 (UniProtKB:Q8TAX9-4)

  12. Represented with two distinct activities:
    • Phospholipid binding (GO:0005543)
    • Wide pore channel activity (GO:0022829)
  13. Both activities correctly occurring in the plasma membrane (GO:0005886)
  14. Part of cytotoxic T cell pyroptotic cell death (GO:1902483)

The model follows a logical causal flow: 1. Perforin (PRF1) enables protein transmembrane transport, which is causally upstream (RO:0002304) of GZMA delivery into the target cell 2. GZMA directly positively regulates (RO:0002629) GSDMB phospholipid binding 3. GSDMB phospholipid binding directly positively regulates (RO:0002629) GSDMB pore-forming activity

This causal chain is well-supported by the literature. According to the key papers (especially PMID:32299851), perforin creates pores in the target cell membrane, allowing granzyme A to enter the cytoplasm where it cleaves GSDMB. The cleaved N-terminal fragment of GSDMB then binds to membrane inner leaflet phospholipids and assembles into pore-forming oligomers, triggering pyroptosis.

Evaluation Based on GO-CAM Curation Guidelines

  1. Molecular Functions, Biological Processes, and Cellular Components:
  2. All activities are correctly annotated with appropriate molecular functions
  3. All are properly linked to their biological processes with 'part_of' relations

  4. Cellular locations are accurately specified with 'occurs_in' relations

  5. Evidence Codes and References:

  6. All annotations are supported by ECO:0000314 (direct assay evidence used in manual assertion)
  7. Citations to relevant primary literature (PMIDs: 32299851, 28154144, 20038786) are provided

  8. All annotations include provenance information

  9. Causal Relations:

  10. The model uses appropriate causal relation predicates (RO:0002629 for 'directly positively regulates' and RO:0002304 for 'causally upstream of, positive effect')
  11. The causal flow follows the correct biological sequence of events

Suggestions for Improvement

While the model is well-constructed overall, here are a few suggestions for improvement:

  1. Additional Biological Context: The model could include the upstream regulation of GSDMB expression by IFN-γ, which is mentioned in the literature as an important factor that increases target cell susceptibility to GZMA-mediated pyroptosis.

  2. Cellular Detail: The model could specify that this process occurs at the immunological synapse between cytotoxic lymphocytes and target cells, which would provide additional cellular context.

  3. Downstream Effects: The model could extend to include some downstream consequences of pyroptosis, such as the release of inflammatory mediators, which would provide a more complete picture of the biological significance of this pathway.

Summary

The GO-CAM model gomodel:6348a65d00000594 is a well-constructed representation of the GZMA-GSDMB pyroptosis pathway that is consistent with current scientific literature. The model accurately captures:

  1. The role of perforin in facilitating GZMA entry into target cells
  2. The proteolytic cleavage of GSDMB by GZMA
  3. The binding of cleaved GSDMB to membrane phospholipids
  4. The formation of membrane pores by GSDMB that lead to pyroptotic cell death

The model follows GO-CAM curation best practices, with appropriate function annotations, cellular locations, biological processes, and causal relationships. The evidence for all annotations is well-documented with appropriate references to the scientific literature.