The mitochondrial protease YME1L regulates type 1 interferon signaling via the cgas-sting pathway in AML
Bibliographic record
Abstract
Abstract Yeast Mitochondrial Escape 1-Like 1 (YME1L) is an inner mitochondrial membrane–anchored ATP-dependent metalloprotease. Here, we investigated its expression and functional role in acute myeloid leukemia (AML). YME1L protein was upregulated in 6 out of 7 AML cell lines and 17 of 23 primary AML patient samples compared to normal hematopoietic stem cells. Analysis of the TCGA dataset revealed that high YME1L mRNA expression correlated with inferior 5-year overall survival in AML patients. To evaluate the essentiality of YME1L in AML, we knocked down the protease in AML cell lines (OCI-AML2, NB4, TEX, and THP-1) with shRNA. YME1L knockdown decreased cell proliferation and clonogenic growth in all tested cell lines. Moreover, YME1L depletion decreased the engraftment of TEX cells into the marrow of immune deficient mice. Interestingly, YME1L knockdown did not induce cell death as measured by Annexin V/PI staining. Rather, YME1L knockdown induced AML differentiation as evidenced by upregulation of CD14, a marker of monocytic differentiation. To understand how YME1L promoted differentiation and decreased proliferation, we performed RNA sequencing of AML cells after YME1L depletion. Knockdown of YME1L upregulated genes associated with type I interferon (IFN) signaling and viral mimicry pathways. By qPCR, we confirmed upregulation of IFN-β, IFN-γ, and interferon-stimulated genes, ISG15, IFI44, IFIT2 after YME1L knockdown. We demonstrated that activation of the IFN signaling was secondary to activation of the cGAS–STING pathway as pharmacologically inhibiting STING abolished the upregulation of IFN signaling after YME1L depletion. We also showed that YME1L knockdown promoted the release of mitochondrial double-stranded DNA into the cytoplasm, a known trigger of IFN signaling. Finally, we demonstrated that inhibiting the VDAC channel with VBIT-4 blocked the upregulation of IFN signaling after YME1L knockdown, thus supporting the functional importance of mtDNA efflux into the cytoplasm as the mechanism explaining increased IFN signaling after YME1L depletion. In summary, we demonstrated that YME1L is overexpressed in a subset of AML samples and is required for AML proliferation and clonogenic growth. YME1L regulates the leakage of mtDNA into the cytoplasm, activation of the cGAS–STING–IFN axis, and AML differentiation. Thus, we have uncovered novel functions for the mitochondrial protease YME1L in AML and new mechanisms for how a mitochondrial protease regulates nuclear gene expression and progenitor function.
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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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".