E3 ubiquitin ligase Cbl-b inhibits NLRP3 inflammasome activation by targeting NLRP3 for ubiquitination (INM6P.405)
Bibliographic record
Abstract
Abstract NLRP3 inflammasome has been shown to be involved in antiviral and antibacterial innate immunity, as well as in the response to adjuvants critical for adaptive immunity. However, inappropriate activation of NLRP3 contributes to deleterious inflammatory syndromes. Although recent studies show that NLRP3 undergoes ubiquitination, the mechanisms for negatively regulating the activation of the NLRP3 inflammasome in response to PAMPs or endogenous DAMPs are largely unknown. In this study, we found that Cbl-b selectively inhibits NLRP3 inflammasome activation, leaving the other key innate response pathways. Further indication of a negative regulation by Cbl-b on NLRP3 inflammasome activity is the finding that LPS injection induces a significant mortality in Cbl-b-/- mice compared to wild-type (WT) controls, and this increased mortality in Cbl-b-/- mice is blocked by an IL-1 receptor antagonist. At the molecular levels, Cbl-b binds to NLRP3 upon LPS priming and ATP stimulation independently of ASC. NLRP3 undergoes ubiquitination in WT macrophages upon NLRP3 inflammasome stimulation, whereas its ubiquitination is impaired in Cbl-b-/- macrophages. Interestingly, NLRP3 inflammasome stimulation also induces Cbl-b tyrosine phosphorylation, which is critical for its ubiquitin ligase activity, thus initiating a negative feedback that controls NLRP3 inflammasome activity. Therefore, we provide a previously-unappreciated function for Cbl-b in regulating NLRP3 inflammasome activation.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".