アポトーシス制御分子Ｂｃｌ－２とＩＰ３受容体による神経可塑性と神経突起伸展の制御

凋亡调节分子 Bcl-2 和 IP3 受体控制神经元可塑性和神经突生长

基本信息

批准号：
13F03793
负责人：
御子柴克彦
金额：
$ 1.47万
依托单位：
Institute of Physical and Chemical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2013
资助国家：
日本
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13F03793/
关键词：
IP3R calcium Bol-2 IRBIT apoptosis Bcl-2

项目摘要

Our research focuses on the interplay between IRBIT, an IP3R-interacting protein discovered in our lab, and the Bcl-2 homolog, Bcl2L10. The zebrafish ortholog of Bcl2L10, Nrz inhibits IP3 fixation on IP3R by interacting with the IP3-binding domain (IP3BD) of the receptor. This mechanism is similar to the one of IRBIT so we studied if these two proteins can be associated to regulate IP3R activity and apoptosis.We have firstly confirmed that Bcl2L10, as its zebrafish ortholog, is able to interact with the IP3BD of IP3R and significantly reduced IP3-induced Ca2+ release. In a second time, we showed that IRBIT and Bcl2L10 interact together and that they bind simultaneously with IP3R. Bcl2L10 strengthens IRBIT interaction with IP3R and the 2 proteins have a synergic effect on IP3-induced Ca2+ release regulation.Interestingly we found that IRBIT and Bcl2L10 are both localized at the mitochondria-associated ER membranes and belong to a protein complex containing IP3R and VDAC. This complex is essential for Ca2+ transfer to mitochondria and play a key role in apoptosis. We found that cells lacking IRBIT are more resistant to diverse apoptotic stress. During apoptosis, IRBIT is dephosphorylated which induces its displacement together with Bcl2L10 from ER membranes. IRBIT dephosphorylation then promotes Ca2+ transfer to the mitochondria which facilitates apoptosis.Finally, we found that IRBIT KO reduces the contact between ER and mitochondria. Then by facilitating ER-mitochondria contact and inhibiting Bcl2L10 interaction with IP3R IRBIT seems to promote Ca2+-dependent apoptosis.

我们的研究重点是IRBIT之间的相互作用，IRBIT是一种在我们的实验室中发现的IP3R相互作用蛋白，而Bcl-2同源物BCL2L10之间的相互作用。 NRZ的BCL2L10的斑马鱼直系同源物通过与受体的IP3结合域（IP3BD）相互作用来抑制IP3对IP3的固定。该机制与IRBIT的一种相似，因此我们研究了这两种蛋白是否可以与IP3R活性和凋亡相关联。我们首先确认Bcl2l10作为其斑马鱼直源性，能够与IP3R的IP3BD相互作用，并显着降低了IP3诱导的Ca2+释放。第二次，我们证明了IRBIT和BCL2L10相互作用，并且它们与IP3R同时结合。 BCL2L10加强与IP3R的IRIT相互作用，2种蛋白质对IP3诱导的Ca2+释放调控具有协同作用。我们发现，IRBIT和BCL2L10都位于线粒体相关的ER膜上，并且属于含有IP3R和VDAC的蛋白质络合物。该复合物对于Ca2+转移到线粒体至关重要，并且在凋亡中起关键作用。我们发现缺乏IRIT的细胞对各种凋亡应激更具抵抗力。在凋亡过程中，IRIT被脱磷酸化，从而诱导其位移与ER膜的BCL2L10一起。然后，IRBIT去磷酸化促进了Ca2+转移到线粒体，从而促进了凋亡。从本文中，我们发现IRBIT KO降低了ER和线粒体之间的接触。然后，通过促进ER-线粒体接触并抑制与IP3R IRIT的BCL2L10相互作用似乎促进了Ca2+依赖性凋亡。