Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Abstract Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca 2+ dynamics by controlling IP 3 receptor (IP 3 R) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IP 3 Rs and preventing pro-apoptotic Ca 2+ release and Bcl-xL sensitizing IP 3 Rs to low [IP 3 ] and promoting pro-survival Ca 2+ oscillations. We here demonstrate that Bcl-xL too inhibits IP 3 R-mediated Ca 2+ release by interacting with the same IP 3 R regions as Bcl-2. Via in silico superposition, we previously found that the residue K87 of Bcl-xL spatially resembled K17 of Bcl-2, a residue critical for Bcl-2’s IP 3 R-inhibitory properties. Mutagenesis of K87 in Bcl-xL impaired its binding to IP 3 R and abrogated Bcl-xL’s inhibitory effect on IP 3 Rs. Single-channel recordings demonstrate that purified Bcl-xL, but not Bcl-xL K87D , suppressed IP 3 R single-channel openings stimulated by sub-maximal and threshold [IP 3 ]. Moreover, we demonstrate that Bcl-xL-mediated inhibition of IP 3 Rs contributes to its anti-apoptotic properties against Ca 2+ -driven apoptosis. Staurosporine (STS) elicits long-lasting Ca 2+ elevations in wild-type but not in IP 3 R-knockout HeLa cells, sensitizing the former to STS treatment. Overexpression of Bcl-xL in wild-type HeLa cells suppressed STS-induced Ca 2+ signals and cell death, while Bcl-xL K87D was much less effective in doing so. In the absence of IP 3 Rs, Bcl-xL and Bcl-xL K87D were equally effective in suppressing STS-induced cell death. Finally, we demonstrate that endogenous Bcl-xL also suppress IP 3 R activity in MDA-MB-231 breast cancer cells, whereby Bcl-xL knockdown augmented IP 3 R-mediated Ca 2+ release and increased the sensitivity towards STS, without altering the ER Ca 2+ content. Hence, this study challenges the current paradigm of divergent functions for Bcl-2 and Bcl-xL in Ca 2+ -signaling modulation and reveals that, similarly to Bcl-2, Bcl-xL inhibits IP 3 R-mediated Ca 2+ release and IP 3 R-driven cell death. Our work further underpins that IP 3 R inhibition is an integral part of Bcl-xL’s anti-apoptotic function.
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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 it