| 研究実績の概要 |
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 mammalian Bcl2L10 is able to interact with IP3R and more precisely with the IP3BD. Moreover, we found that Bcl2L10 significantly reduced IP3-induced calcium release. Thus Bcl2L10 acts as its zebrafish ortholog and then reduces calcium release through IP3R by interacting with the IP3BD.
In a second time, we showed that IRBIT and Bcl2L10 do not seem to compete for the binding with the IP3BD suggesting they can interact simultaneously with IP3R. More interestingly, we found that IRBIT and Bcl2L10 can directly interact together raising the idea that IRBIT and Bcl2L10 can form a complex on the IP3BD.
We also studied the subcellular localization of Bcl2L10 and IRBIT. We found that these proteins can be localized at the mitochondria-associated endoplasmic reticulum membranes. This portion of the ER is essential for Ca2+ transfer to mitochondria and play a crucial role in apoptosis. We then performed experiments to assess if IRBIT may play a role in apoptosis and we found that cells lacking IRBIT are more resistant to diverse apoptotic stress. We will then now look if this effect of IRBIT is related to its interaction with Bcl2L10 and IP3R.
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