IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact
IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact
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DOI：
10.7554/elife.19896
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发表时间：
2016-12-20
期刊：
影响因子：
7.7
通讯作者：
Mikoshiba, Katsuhiko
中科院分区：
文献类型：
--
作者：
Bonneau, Benjamin;Ando, Hideaki;Mikoshiba, Katsuhiko
IRBIT是一种与IP3受体（IP3R）的肌醇1,4,5-三磷酸（IP3）结合袋相互作用的分子，而抗凋亡蛋白Bcl2l10则与IP3结合域的另一部分结合。本研究表明，Bcl2l10和IRBIT相互作用，在生理状态下对IP3R产生加性抑制。此外，我们发现这些蛋白在线粒体相关膜（MAMs）的复合物中结合，它们的相互作用参与细胞凋亡调节。MAMs是Ca2+在内质网（ER）和线粒体之间转移的热点，通过线粒体中的IP3R大量释放Ca2+诱导细胞死亡。我们发现在凋亡应激下，IRBIT被去磷酸化，成为Bcl2l10的抑制剂。此外，IRBIT促进内质网线粒体接触。我们的研究结果表明，通过抑制Bcl2l10活性并促进内质网和线粒体之间的接触，IRBIT促进了大量Ca2+向线粒体的转移并促进了细胞凋亡。这项工作随后将IRBIT描述为细胞死亡的新调节剂。
IRBIT is a molecule that interacts with the inositol 1,4,5-trisphosphate (IP3)-binding pocket of the IP3 receptor (IP3R), whereas the antiapoptotic protein, Bcl2l10, binds to another part of the IP3-binding domain. Here we show that Bcl2l10 and IRBIT interact and exert an additive inhibition of IP3R in the physiological state. Moreover, we found that these proteins associate in a complex in mitochondria-associated membranes (MAMs) and that their interplay is involved in apoptosis regulation. MAMs are a hotspot for Ca2+ transfer between endoplasmic reticulum (ER) and mitochondria, and massive Ca2+ release through IP3R in mitochondria induces cell death. We found that upon apoptotic stress, IRBIT is dephosphorylated, becoming an inhibitor of Bcl2l10. Moreover, IRBIT promotes ER mitochondria contact. Our results suggest that by inhibiting Bcl2l10 activity and promoting contact between ER and mitochondria, IRBIT facilitates massive Ca2+ transfer to mitochondria and promotes apoptosis. This work then describes IRBIT as a new regulator of cell death.