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6438950a00000032 Human metapneumovirus M2 2 inhibition of IRF7 Human Metapneumovirus

Now, I'll review the GO-CAM model in detail based on all the information I've gathered.

Review of GO-CAM Model: gomodel:6438950a00000032

Summary of the Model

This GO-CAM model is titled "Human metapneumovirus M2-2 inhibition of IRF7 (Human-Metapneumovirus)" and depicts interactions between human metapneumovirus (HMPV) M2-2 protein and the host innate immune response.

Model Components

The model consists of four main activities: 1. HMPV M2-2 protein (UniProtKB:Q6WB96) - Protein sequestering activity (GO:0140311) occurring in the cytoplasm (GO:0005737) 2. TBK1 (UniProtKB:Q9UHD2) - Protein serine/threonine kinase activity (GO:0004674) occurring in the cytoplasm (GO:0005737) 3. TLR9 (UniProtKB:Q9NR96) - Pattern recognition receptor activity (GO:0038187) occurring in the endoplasmic reticulum (GO:0005783) 4. IRF7 (UniProtKB:Q92985) - DNA-binding transcription factor activity (GO:0000981) occurring in chromatin (GO:0000785)

Causal Relationships

  1. HMPV M2-2 directly negatively regulates (RO:0002630) IRF7
  2. TBK1 directly positively regulates (RO:0002629) IRF7
  3. TLR9 provides input for (RO:0002407) TBK1

Evidence

The model is supported by experimental evidence from several scientific papers: - PMID:28768858 - Primary paper showing that HMPV M2-2 protein acts as a negative regulator of IFN-alpha production by inhibiting IRF7 phosphorylation - PMID:25636800 - Evidence for TBK1-mediated phosphorylation of IRF7 - PMID:14716310 - Evidence for TLR9 subcellular localization and function - PMID:23857366 - Evidence for TLR9 role in signaling pathway - PMID:14703513 - Evidence for TBK1 in cytoplasmic localization - PMID:17404045 - Evidence for IRF7 transcription factor activity - PMID:11473119 - Evidence for IRF7 chromatin localization - PMID:16979567 - Evidence for IRF7 role in interferon production

Biological Context

This model represents how the HMPV M2-2 protein interferes with the host innate immune response. The pathway normally involves TLR9 sensing viral/bacterial DNA in endosomes, leading to TBK1 activation, which then phosphorylates IRF7. Activated IRF7 translocates to the nucleus and induces type I interferon production. The HMPV M2-2 protein disrupts this pathway by directly binding to IRF7 and preventing its phosphorylation by TBK1, thereby inhibiting the host interferon response.

Review Analysis

Strengths of the Model

  1. Scientific Accuracy: The model accurately represents the core mechanism of HMPV M2-2 protein's inhibitory effect on IRF7 as described in the primary literature (PMID:28768858).

  2. Well-evidenced: Each component and relationship in the model is supported by appropriate evidence from peer-reviewed literature.

  3. Clear Biological Context: The model clearly depicts how a viral protein disrupts a specific host immune signaling pathway.

  4. Appropriate Use of GO Terms: The molecular function terms assigned to each protein are appropriate based on their known functions.

Areas for Improvement

  1. Complex Annotation: Based on the GO-CAM guidelines for complex annotation, there may be opportunities to improve the representation of protein complexes or multi-protein interactions. The M2-2 interaction with IRF7 is a direct binding interaction according to the literature, which is correctly represented in the model.

  2. Subcellular Localization Accuracy: According to the literature, TLR9 is initially localized to the ER (as correctly shown in the model) but relocates to endosomes/lysosomes upon CpG DNA binding. The model could potentially be enhanced to show this translocation, though for simplicity the current representation is acceptable.

  3. Signal Transduction Completeness: The signaling pathway from TLR9 activation to IRF7 phosphorylation involves additional components like MyD88 and TRAF6 that aren't represented in the current model. While the model correctly represents the core pathway affected by M2-2, including these intermediary steps would make it more complete.

  4. Phosphorylation Events: The model represents that TBK1 directly positively regulates IRF7, but could be more specific to indicate that this regulation occurs via phosphorylation specifically at Ser477 (as shown in PMID:28768858).

  5. Additional Outcomes: The biological process of "negative regulation of type I interferon production" (GO:0032480) is correctly annotated to M2-2, but the model could potentially include the downstream effects on interferon production more explicitly.

Recommendations

  1. Consider Adding Molecular Detail: Consider adding the specific phosphorylation site of IRF7 (Ser477) as mentioned in the primary paper to provide more molecular detail.

  2. Expand the Signaling Pathway: If the goal is a more comprehensive model, consider adding MyD88 and TRAF6 as intermediate steps between TLR9 and TBK1 activation.

  3. Add Downstream Effects: Consider expanding the model to show how IRF7 inhibition leads to reduced interferon production, potentially including interferon genes as outputs of the pathway.

  4. Clarify Cellular Locations: Consider adding a more detailed representation of TLR9 translocation from the ER to endosomes upon activation, as this is an important aspect of its signaling mechanism.

Final Assessment

The GO-CAM model "Human metapneumovirus M2-2 inhibition of IRF7 (Human-Metapneumovirus)" is scientifically accurate and well-supported by evidence. It effectively captures the core mechanism by which HMPV M2-2 protein disrupts host innate immune signaling by targeting IRF7. The model follows GO-CAM best practices regarding evidence citations and causal relationships.

While there are opportunities to expand the model with additional molecular detail and pathway components, the current representation is parsimonious and clearly communicates the essential biological mechanism. This model provides valuable insight into how human metapneumovirus evades host immune responses.