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663d668500001246 Pyroptotic cell death mediated by GSDMD and NINJ1 Human

Now let's analyze the GO-CAM model in detail to provide a comprehensive review:

Review of GO-CAM Model: gomodel:663d668500001246 - "Pyroptotic cell death mediated by GSDMD and NINJ1 (Human)"

Overview

This model represents pyroptotic cell death mediated by GSDMD (Gasdermin D) and NINJ1 (Ninjurin-1) in humans. Pyroptosis is a form of inflammatory programmed cell death characterized by cell swelling, membrane pore formation, and eventual plasma membrane rupture, leading to the release of inflammatory cytokines and cellular contents.

Strengths of the Model

  1. Well-supported by evidence: The model cites multiple recent publications as evidence for each association, enhancing its reliability. The literature referenced includes key papers about NINJ1's role in plasma membrane rupture during pyroptotic cell death.

  2. Clear pathway depiction: The model effectively captures the sequential steps in pyroptotic cell death, from caspase-1 activation to GSDMD pore formation to NINJ1-mediated membrane rupture.

  3. Appropriate use of causal connections: The model correctly uses the RO:0002629 (directly positively regulates) predicate to connect activities in the cascade.

  4. Correct cellular locations: All activities are assigned appropriate cellular locations (cytosol for caspase, plasma membrane for GSDMD and NINJ1).

  5. Correct integration of recent research: The model accurately reflects recent discoveries about NINJ1's role in the final stage of pyroptosis (plasma membrane rupture), which was only elucidated in detail in recent years (2021-2023).

Areas for Improvement

  1. Missing input molecules: While the model shows CASP1 with cysteine-type endopeptidase activity, it doesn't include the upstream inflammasome activation that triggers CASP1 activity. Including this would provide more context about what initiates this pathway.

  2. Incomplete molecular mechanism details: The model correctly identifies that phosphatidylinositol binding activities are important for GSDMD function, but could benefit from including details about GSDMD cleavage by CASP1 to generate the active N-terminal fragment, which is mentioned in the literature you provided.

  3. Absent interleukin release: The literature indicates that the release of mature IL-1β and IL-18 occurs through GSDMD pores, which happens before complete membrane rupture. This could be included as an additional outcome or process in the model.

  4. Missing regulation by other proteins: The studies on NINJ1 mention potential regulatory factors and conditions that affect its function, which could be added to provide a more complete picture.

Detailed Analysis of Model Components

1. CASP1 Activity

  • Activity: GO:0004197 (cysteine-type endopeptidase activity)
  • Enabled by: UniProtKB:P29466 (CASP1 Hsap)
  • Occurs in: GO:0005829 (cytosol)
  • Part of: GO:0051604 (protein maturation)
  • Evidence: ECO:0000314 (direct assay evidence used in manual assertion) with PMID:32109412
  • Assessment: Correctly represented, but could benefit from including the inflammasome complex that activates CASP1.

2. GSDMD Activities

The model shows GSDMD with two different activities: - Activity 1: GO:0070273 (phosphatidylinositol-4-phosphate binding) - Activity 2: GO:0005546 (phosphatidylinositol-4,5-bisphosphate binding) - Both enabled by: UniProtKB:P57764 (GSDMD Hsap) - Occurs in: GO:0005886 (plasma membrane) - Part of: GO:0141201 (pyroptotic cell death) - Evidence: ECO:0000314 (direct assay evidence used in manual assertion) with PMID:36227980 - Assessment: Correctly represented, but could explicitly include the cleavage step creating GSDMD-NT fragment.

3. GSDMD Pore Formation

  • Activity: GO:0022829 (wide pore channel activity)
  • Enabled by: UniProtKB:P57764 (GSDMD Hsap)
  • Occurs in: GO:0005886 (plasma membrane)
  • Part of: GO:0050729 (positive regulation of inflammatory response)
  • Evidence: ECO:0000314 (direct assay evidence used in manual assertion) with PMID:33883744
  • Assessment: Well represented, but could benefit from explicit connection to the release of IL-1β and IL-18 through these pores.

4. NINJ1 Activity

  • Activity: GO:0140912 (membrane destabilizing activity)
  • Enabled by: UniProtKB:Q92982 (NINJ1 Hsap)
  • Occurs in: GO:0005886 (plasma membrane)
  • Part of: GO:0141201 (pyroptotic cell death)
  • Evidence: Multiple ECO:0000314 references with PMIDs: 33472215, 36468682, 37196676, 37198476
  • Assessment: Well represented, supported by multiple recent publications.

5. Causal Associations

The model correctly represents the sequential nature of the pathway: - CASP1 endopeptidase activity → GSDMD phosphatidylinositol binding activities - GSDMD phosphatidylinositol binding activities → GSDMD pore formation - GSDMD pore formation → NINJ1 membrane destabilizing activity

All use RO:0002629 (directly positively regulates), which is appropriate based on the literature.

Summary and Recommendations

This GO-CAM model accurately represents the current understanding of GSDMD and NINJ1's roles in pyroptotic cell death, particularly the sequential activities leading to membrane rupture. The model is well-supported by recent scientific evidence and correctly represents the cellular locations and causal relationships between components.

Recommendations for improvement:

  1. Add the upstream inflammasome activation that triggers CASP1 activity, possibly including NLRP3, ASC, and other relevant components.

  2. Explicitly represent the cleavage of GSDMD by CASP1 to generate the active N-terminal fragment (GSDMD-NT).

  3. Include the release of mature IL-1β and IL-18 through GSDMD pores as an outcome or part of the inflammatory response process.

  4. Consider adding details about oligomerization of NINJ1 and GSDMD, as described in the recent structural studies.

  5. Include additional regulatory factors that affect the activity of these proteins, as mentioned in the recent literature.

Overall, this is a high-quality model that effectively represents our current understanding of pyroptotic cell death mediated by GSDMD and NINJ1. The suggested improvements would further enhance its comprehensiveness and utility.