IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact

Benjamin Bonneau; Hideaki Ando; Katsuhiro Kawaai; Matsumi Hirose; Hiromi Takahashi-Iwanaga; Katsuhiko Mikoshiba

doi:10.7554/eLife.19896

IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact

Elife. 2016 Dec 20:5:e19896. doi: 10.7554/eLife.19896.

Authors

Benjamin Bonneau¹, Hideaki Ando¹, Katsuhiro Kawaai¹, Matsumi Hirose¹, Hiromi Takahashi-Iwanaga², Katsuhiko Mikoshiba¹

Affiliations

¹ Laboratory for Developmental Neurobiology, RIKEN Brain Science institute, Wako-shi, Japan.
² Department of Anatomy, School of Medicine Hokkaido University, Sapporo, Japan.

Abstract

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.

Keywords: Bcl-2; IP3R; apoptosis; calcium; cell biology; mitochondria-associated membranes; none.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Cell Line
Endoplasmic Reticulum / metabolism*
Humans
Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors
Lectins, C-Type / metabolism*
Membrane Proteins / metabolism*
Mice
Mitochondria / metabolism*
Protein Binding
Protein Interaction Mapping
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*

Substances

BCL2-like 10 protein
CLECL1 protein, human
Inositol 1,4,5-Trisphosphate Receptors
Lectins, C-Type
Membrane Proteins
Proto-Oncogene Proteins c-bcl-2

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.