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

我们的研究重点是我们实验室发现的ip3r相互作用蛋白IRBIT与Bcl-2同源物Bcl2L10之间的相互作用。作为Bcl2L10的斑马鱼同源物，Nrz通过与受体的IP3结合域（IP3BD）相互作用抑制IP3在IP3R上的固定。这种机制与IRBIT相似，因此我们研究了这两种蛋白是否可以关联调节IP3R活性和细胞凋亡。我们首先证实，Bcl2L10作为其在斑马鱼中的同源物，能够与IP3R的IP3BD相互作用，并显著降低ip3诱导的Ca2+释放。在第二次研究中，我们发现IRBIT和Bcl2L10相互作用，并同时与IP3R结合。Bcl2L10增强了IRBIT与IP3R的相互作用，这两种蛋白在ip3诱导的Ca2+释放调控中具有协同作用。有趣的是，我们发现IRBIT和Bcl2L10都定位于线粒体相关的ER膜，属于含有IP3R和VDAC的蛋白质复合物。这个复合体是Ca2+转移到线粒体所必需的，在细胞凋亡中起关键作用。我们发现缺乏IRBIT的细胞更能抵抗各种凋亡应激。在细胞凋亡过程中，IRBIT被去磷酸化，导致其与Bcl2L10一起从内质网膜上移位。然后，IRBIT去磷酸化促进Ca2+转移到线粒体，从而促进细胞凋亡。最后，我们发现IRBIT KO减少了内质网和线粒体之间的接触。然后，通过促进er -线粒体接触和抑制Bcl2L10与IP3R的相互作用，IRBIT似乎促进了Ca2+依赖性细胞凋亡。

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.