title: IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact.
abstract: IRBIT is a molecule that interacts with the inositol 1,4,5-trisphosphate (IP3)-binding pocket of the IP3receptor (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.
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science institute, Wako-shi, Japan.
authors.forename: Benjamin
authors.identifier: 0000-0003-2302-5369
authors.initials: B
authors.lastname: Bonneau
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science institute, Wako-shi, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ando
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science institute, Wako-shi, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kawaai
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science institute, Wako-shi, Japan.
authors.forename: Matsumi
authors.initials: M
authors.lastname: Hirose
authors.affiliation: Department of Anatomy, School of Medicine Hokkaido University, Sapporo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Takahashi-Iwanaga
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science institute, Wako-shi, Japan.
authors.forename: Katsuhiko
authors.identifier: 0000-0002-3487-6970
authors.initials: K
authors.lastname: Mikoshiba
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D037181:Lectins, C-Type / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*
chemical_list: C117144:BCL2-like 10 protein; C470184:CLECL1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D037181:Lectins, C-Type; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: Bcl-2; IP3R; apoptosis; calcium; cell biology; mitochondria-associated membranes; none