Interaction between the mitochondrial protein BNIP3 and caspase-2 enhances cell death and DNA fragmentation
Bibliographic record
Abstract
BNIP3 is a cell death-inducing mitochondrial protein that is part of a Bcl-2 subfamily with NIX and ceBNIP3. BNIP3-induced cell death morphologically resembles necrosis that is characterized by rapid plasma membrane damage and mitochondrial dysfunction in the early stages, followed by DNA fragmentation and chromatin condensation characteristic of apoptotic cell death in the later stages. DNA fragmentation during most types of apoptosis is predominantly due to caspase-3 activation. However, BNIP3-induced cell death is independent of caspase-3 activity, thus the mechanism of BNIP3-induced DNA fragmentation remains unknown. Co-immunoprecipitation analysis revealed an interaction between BNIP3, NIX, and caspase-2. The interaction is unique in that it is not mediated through the caspase-2 prodomain. Caspases-1, -8, and -9, which have homologous prodomains to caspase-2, do not bind BNIP3 or NIX, indicating specificity for caspase-2. Further structural analysis indicated that the transmembrane domain and NH2-terminus of BNIP3, which mediate binding to Bcl-2 and Bcl-XL, are not required for binding caspase-2. An ' in vitro' caspase assay detected activation of endogenous caspase-2 in BNIP3-transfected cells. This activation corresponded with enhanced cell death and DNA fragmentation in cells co-expressing BNIP3 and caspase-2. Furthermore, both a broad-spectrum caspase inhibitor and a caspase-2-specific inhibitor blocked NIP3-induced DNA fragmentation 'in vivo', and cleavage of a caspase-2-specific substrate 'in vitro', indicating a role for caspase-2 in BNIP3-induced cell death. Taken together, our results suggest that BNIP3 induces DNA fragmentation and subsequent cell death through a novel mechanism involving the specific recruitment and activation of caspase-2.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".