ZNF334 truncation mutation drives cold-induced autoinflammation
Bibliographic record
Abstract
The role of zinc finger protein 334 (ZNF334) in immunological processes remains unknown. We identified a ZNF334 truncation mutation (p.Thr399fs) in a rare case of late-onset cold-induced autoinflammatory disease with elevated TNF-α, IL-1β, IL-6, and extracellular heat shock protein 90 (eHsp90) plasma levels and progressive sensorineural hearing loss. Using patient-derived monocytes and CRISPR/Cas9-edited THP-1 monocytes with a ZNF334 truncation mutation, we discovered that the mutation reduced the interaction between ZNF334 and Hsp90, diminished the endogenous levels of the cold stress regulators Hsp90 and transient receptor potential melastatin 8 (TRPM8), disrupted ER protein folding response and redox homeostasis, and increased cold-induced NF-κB activation and secretion of the proinflammatory TRPM8+ mitochondria-containing extracellular vesicles in monocytes. Long-term cold avoidance alleviated the patient's cold-induced symptoms. In addition, treatment of ZNF334-truncated THP-1 cells with an Hsp90 inhibitor prevented cold-induced TNF and NLRP3 upregulations. Our findings suggest ZNF334 as an essential regulator of cold-induced inflammation and oxidative stress, and Hsp90 ATPase inhibitors might be effective in the treatment of autoinflammatory diseases induced by repeated mild cold exposure.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".