Skip to content

After reviewing all the information, I can now conduct a thorough review of the GO-CAM model gomodel:65f3ae5c00000585.

GO-CAM Review: gomodel:65f3ae5c00000585

Overview of the Model

The model titled "Ufmylation of CYB5R3 promotes reticulophagy and CYB5R3 degradation (Human)" depicts a biological process involving the UFM1 system in the regulation of ER-phagy (reticulophagy) in humans. The model shows how UFM1, a ubiquitin-like modifier, is conjugated to CYB5R3 (NADH-cytochrome b5 reductase 3) through an enzymatic cascade involving the E3 UFM1-protein ligase complex, which promotes lysosomal degradation of CYB5R3.

Biological Content Assessment

The model accurately represents the recent findings from Ishimura et al. (2022) [PMID:36543799], which identified CYB5R3 as a substrate for the UFM1 system. The scientific content is consistent with current literature:

  1. The UFM1 system consists of E1 (not shown in the model), E2 (not shown), and E3 (represented by UFL1 and CDK5RAP3) components.
  2. CYB5R3 is accurately depicted as being ufmylated by UFL1 (E3 UFM1-protein ligase 1).
  3. DDRGK1 (shown as UFBP1 in the literature) is correctly shown as part of the E3 ligase complex.
  4. The model shows UFSP2 as having deUFMylase activity, which is accurate.
  5. The connections between these components reflect our current understanding of this pathway.

Recent research by DaRosa et al. (2024) [PMID:38383785] and Makhlouf et al. (2024) [PMID:38383789] provides additional context for the UFM1 system's role in ribosome recycling, which is tangential to this model's specific focus on CYB5R3 ufmylation and degradation.

Model Structure Evaluation

The model follows GO-CAM best practices:

  1. Activities are properly connected: The model shows a coherent flow of activities using appropriate causal relations:
  2. CDK5RAP3's activity provides input for UFL1's activity (RO:0002413)
  3. UFL1's activity directly positively regulates CYB5R3's activity (RO:0002629)
  4. UFSP2's activity directly negatively regulates CYB5R3's activity (RO:0002630)

  5. DDRGK1's activity directly negatively regulates CYB5R3's activity (RO:0002630)

  6. Molecular function terms are appropriate:

  7. UFL1: "E3 UFM1-protein ligase activity" (GO:0061666)
  8. UFSP2: "deUFMylase activity" (GO:0071567)
  9. DDRGK1: "UFM1-modified protein reader activity" (GO:0141185)
  10. CDK5RAP3: "ubiquitin-like ligase-substrate adaptor activity" (GO:1990756)

  11. CYB5R3: "cytochrome-b5 reductase activity, acting on NAD(P)H" (GO:0004128)

  12. Biological process terms are appropriate:

  13. UFL1 and CDK5RAP3 are part of "protein ufmylation" (GO:0071569)
  14. DDRGK1 is part of "positive regulation of reticulophagy" (GO:0140501)
  15. UFSP2 is part of "negative regulation of proteolysis involved in protein catabolic process" (GO:1903051)

  16. CYB5R3 is part of "blood circulation" (GO:0008015)

  17. Cellular location information is included:

  18. UFL1, DDRGK1, and CYB5R3 are correctly localized to the endoplasmic reticulum membrane (GO:0005789)

Quality Control Assessment

Strengths:

  1. The model accurately represents the core UFM1 system components involved in CYB5R3 ufmylation.
  2. The causal relationships between activities are appropriate.
  3. Evidence codes and PMIDs are properly used to support the annotations.
  4. The model captures the biological context of reticulophagy and CYB5R3 degradation.

Issues and Recommendations:

  1. Incomplete representation of the E1 and E2 components: The model doesn't include UBA5 (E1) and UFC1 (E2), which are essential parts of the UFM1 conjugation system. While focusing on the E3 components is reasonable for simplicity, it might be worth noting their absence.

  2. Biological process annotation for CYB5R3: CYB5R3 is annotated with "blood circulation" (GO:0008015), which, while not incorrect, doesn't directly relate to its role in this specific context. A more contextually relevant biological process term such as "reticulophagy" (GO:0061709) would better reflect its role in this model.

  3. Evidence code for CYB5R3's biological process: The evidence code for CYB5R3's involvement in blood circulation is ECO:0000304 (author statement supported by traceable reference), but the PMID cited (1400360) is from 1992 and doesn't directly relate to the reticulophagy context. A more recent reference specifically addressing CYB5R3's role in ER-phagy would be more appropriate.

  4. DDRGK1 naming: The model uses DDRGK1, while recent literature often refers to this protein as UFBP1. For clarity, it might be helpful to note this alias.

Final Assessment

This GO-CAM model presents a scientifically accurate representation of the UFM1 system's role in CYB5R3 ufmylation and subsequent degradation through reticulophagy. The model follows GO-CAM best practices and effectively communicates the biological process. With minor adjustments to the biological process annotation for CYB5R3 and possibly the inclusion of E1 and E2 components, this model would provide an even more comprehensive view of this pathway.

The model successfully captures a specific aspect of the UFM1 system that has important implications for ER homeostasis and potentially for neuronal development, as suggested by the source literature. The recent findings on the UFM1 system's role in ribosome recycling provide additional context but don't directly impact this model's validity.