Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis
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-apopto...
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Veröffentlicht in: | Cell death and differentiation 2022-04, Vol.29 (4), p.788-805 |
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Zusammenfassung: | 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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ISSN: | 1350-9047 1476-5403 |
DOI: | 10.1038/s41418-021-00894-w |