Deciphering CLEC12A Negative Regulation of Neutrophils through Protein-Protein Interaction Network and Functional Enrichment Analyses
Bibliographic record
Abstract
CLEC12A is a negative regulator of myeloid cell activation in inflammation-related diseases. In the absence of CLEC12A, myeloid cells such as neutrophils respond more robustly to pro-inflammatory stimuli, leading to exacerbated inflammation in CLEC12A knock-out mice challenged with arthritis-inducing stimuli. Similarly, lower CLEC12A expression in early rheumatoid arthritis patients also correlates with increased disease activity. While CLEC12A plays a key role in inflammation-related diseases, the mechanisms that regulate myeloid function are poorly understood. Using protein-protein network and functional enrichment approaches, complemented by validating experiments, we provide insight into CLEC12A-regulated molecular pathways and how they are interconnected. The CLEC12A protein-protein interaction network (CLEC12A PPIN) was constructed by querying and selectively filtering the BioGRID database. Functional enrichment analyses were performed on both first- and second-degree interactors. Additionally, results from phosphoproteomics experiments conducted on human neutrophils were incorporated into the network. The CLEC12A first-degree PPIN comprises 32 proteins that interact with CLEC12A. Enrichment analysis revealed that 12 of these 32 primary interactors belong to the SNARE family, while 4 are signaling proteins. Enrichment visualization conducted with our Bioconductor enrichViewNet package reinforces the importance of the SNARE proteins. Integrating the phosphoproteomics results into the CLEC12A second-degree PPIN identified potential signaling pathways regulated by CLEC12A. The involvement of signaling pathways enriched in the CLEC12A second-degree PPIN was experimentally validated. Our experimental data provide evidence for the role of ERK in regulating pro- and anti-inflammatory cytokine release by CLEC12A. The CLEC12A PPIN revealed that intracellular vesicular trafficking and MAP kinases are key mechanisms through which CLEC12A negatively regulates neutrophil activation. Our findings demonstrate that the CLEC12A PPIN can identify important CLEC12A-regulated pathways that may be associated to immune-mediated diseases. The insights provided by CLEC12A PPIN analyses, enrichment analyses, and visualization have accelerated discovery by facilitating the design of disease sub-networks and biological experiments to decipher the mechanism of action of CLEC12A and its role in immune-mediated diseases.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".