TY - JOUR
T1 - IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact
AU - Bonneau, Benjamin
AU - Ando, Hideaki
AU - Kawaai, Katsuhiro
AU - Hirose, Matsumi
AU - Takahashi-Iwanaga, Hiromi
AU - Mikoshiba, Katsuhiko
N1 - Funding Information:
We thank Pr. Germain Gillet for providing pSG5-FLAG-Bcl2l10 vector. This work was supported by RIKEN (Special Postdoctoral Researcher [SPDR]), the Japan Society for the Promotion of Science(JSPS) (International Research Fellow) and JST International Cooperative Research Project–Solution Oriented Research for Science and Technology. Japan Society for the Promotion of Science Benjamin Bonneau RIKEN Benjamin Bonneau The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© Bonneau et al.
PY - 2016/12/20
Y1 - 2016/12/20
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.19896
DO - 10.7554/eLife.19896
M3 - Article
C2 - 27995898
AN - SCOPUS:85006931176
SN - 2050-084X
VL - 5
JO - eLife
JF - eLife
IS - DECEMBER2016
M1 - e19896
ER -