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

我们的研究集中在伊尔比特，在我们的实验室发现的IP 3R相互作用蛋白，和Bcl-2同源物，Bcl 2L 10之间的相互作用。Bcl 2L 10的斑马鱼直系同源物Nrz通过与受体的IP 3结合结构域（IP 3BD）相互作用来抑制IP 3在IP 3R上的固定。我们首次证实了Bcl 2L 10作为其在斑马鱼中的直系同源物，能够与IP 3R的IP 3BD相互作用，显著降低IP 3诱导的Ca ~（2+）释放。在第二次，我们表明，伊尔比特和Bcl 2 L10相互作用，他们同时结合IP 3 R。有趣的是，我们发现伊尔比特和Bcl 2L 10都定位于内质网膜上，属于一个含有IP 3R和VDAC的蛋白复合物。该复合物是Ca 2+向线粒体转移所必需的，并在细胞凋亡中起关键作用。我们发现缺乏伊尔比特的细胞对不同的凋亡应激更有抵抗力。在细胞凋亡过程中，伊尔比特被去磷酸化，这诱导其与Bcl 2 L10一起从ER膜上移位。伊尔比特去磷酸化促进Ca ~（2+）向线粒体的转移，从而促进细胞凋亡。最后，我们发现伊尔比特KO减少了ER与线粒体的接触。通过促进ER-线粒体接触和抑制Bcl 2 L10与IP 3 R的相互作用，伊尔比特似乎促进了Ca 2+依赖的细胞凋亡。

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.