Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis

doi:10.1038/s41418-021-00894-w

KMS > 免疫化学研究所 > PI研究组 > Katsuhiko Mikoshiba组

	Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis
	Rosa, Nicolas 1,2; Ivanova, Hristina 1,2; Wagner, Larry E.3; Kale, Justin 4; La Rovere, Rita 1,2; Welkenhuyzen, Kirsten 1,2; Louros, Nikolaos 5,6; Karamanou, Spyridoula 7; Shabardina, Victoria 8; Lemmens, Irma 9,10; Vandermarliere, Elien 11; Hamada, Kozo12 ; Ando, Hideaki 13; Rousseau, Frederic 5,6; Schymkowitz, Joost 5,6; Tavernier, Jan 9,10; Mikoshiba, Katsuhiko12,14 ; Economou, Anastassios 7; Andrews, David W.4; Parys, Jan B.1,2; Yule, David, I 3; Bultynck, Geert 1,2
	2021
发表期刊	CELL DEATH AND DIFFERENTIATION
ISSN	1350-9047
EISSN	1476-5403
DOI	10.1038/s41418-021-00894-w
摘要	Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca2+ dynamics by controlling IP3 receptor (IP3R) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IP(3)Rs and preventing pro-apoptotic Ca2+ release and Bcl-xL sensitizing IP(3)Rs to low [IP3] and promoting pro-survival Ca2+ oscillations. We here demonstrate that Bcl-xL too inhibits IP3R-mediated Ca2+ release by interacting with the same IP3R 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 IP3R-inhibitory properties. Mutagenesis of K87 in Bcl-xL impaired its binding to IP3R 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 IP3R single-channel openings stimulated by sub-maximal and threshold [IP3]. Moreover, we demonstrate that Bcl-xL-mediated inhibition of IP(3)Rs contributes to its anti-apoptotic properties against Ca2+-driven apoptosis. Staurosporine (STS) elicits long-lasting Ca2+ elevations in wild-type but not in IP3R-knockout HeLa cells, sensitizing the former to STS treatment. Overexpression of Bcl-xL in wild-type HeLa cells suppressed STS-induced Ca2+ 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 IP3R activity in MDA-MB-231 breast cancer cells, whereby Bcl-xL knockdown augmented IP3R-mediated Ca2+ release and increased the sensitivity towards STS, without altering the ER Ca2+ content. Hence, this study challenges the current paradigm of divergent functions for Bcl-2 and Bcl-xL in Ca2+-signaling modulation and reveals that, similarly to Bcl-2, Bcl-xL inhibits IP3R-mediated Ca2+ release and IP3R-driven cell death. Our work further underpins that IP3R inhibition is an integral part of Bcl-xL's anti-apoptotic function.
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收录类别	SCIE
语种	英语
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
WOS类目	Biochemistry & Molecular Biology ; Cell Biology
WOS记录号	WOS:000715639400001
出版者	SPRINGERNATURE
原始文献类型	Article; Early Access
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/130308
专题	免疫化学研究所_PI研究组_Katsuhiko Mikoshiba组
通讯作者	Bultynck, Geert
作者单位	1.Katholieke Univ Leuven, Lab Mol & Cellular Signaling, Dept Cellular & Mol Med, Campus Gasthuisberg O-N-1 Box 802,Herestr 49, B-3000 Leuven, Belgium; 2.Leuven Kanker Inst, Campus Gasthuisberg O-N-1 Box 802,Herestr 49, B-3000 Leuven, Belgium; 3.Univ Rochester, Sch Med & Dent, Dept Pharmacol & Physiol, 601 Elmwood Ave Box 711, Rochester, NY 14642 USA; 4.Univ Toronto, Sunnybrook Res Inst, Biol Sci, Toronto, ON M4N 3M5, Canada; 5.VIB Ctr Brain & Dis Res, Campus Gasthuisberg O-N 1bis Box 802,Herestr 49, B-3000 Leuven, Belgium; 6.Katholieke Univ Leuven, Switch Lab, Dept Cellular & Mol Med, Campus Gasthuisberg O-N 1bis Box 802,Herestr 49, B-3000 Leuven, Belgium; 7.Katholieke Univ Leuven, Lab Mol Bacteriol, Dept Microbiol & Immunol, Rega Inst Med Res, Campus Gasthuisberg,POB 1037,Herestr 49, B-3000 Leuven, Belgium; 8.Univ Pompeu Fabra, CSIC, Inst Evolutionary Biol, Passeig Maritim Barceloneta 37-49, Barcelona 08003, Spain; 9.Univ Ghent, Dept Biomol Med, Cytokine Receptor Lab, Fac Med & Hlth Sci, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium; 10.VIB, Ctr Med Biotechnol, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium; 11.VIB, VIB UGent Ctr Med Biotechnol, B-9000 Ghent, Belgium; 12.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China; 13.RIKEN, Brain Sci Inst, Lab Dev Neurobiol, 2-1 Hirosawa, Wako, Saitama 3510198, Japan; 14.Toho Univ, Fac Sci, Miyama 2-2-1, Funabashi, Chiba 2748510, Japan
推荐引用方式 GB/T 7714	Rosa, Nicolas,Ivanova, Hristina,Wagner, Larry E.,et al. Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis[J]. CELL DEATH AND DIFFERENTIATION,2021.
APA	Rosa, Nicolas.,Ivanova, Hristina.,Wagner, Larry E..,Kale, Justin.,La Rovere, Rita.,...&Bultynck, Geert.(2021).Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis.CELL DEATH AND DIFFERENTIATION.
MLA	Rosa, Nicolas,et al."Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis".CELL DEATH AND DIFFERENTIATION (2021).