title: TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis.
abstract: Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX-inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane.
authors.affiliation: Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: D
authors.initials: D
authors.lastname: Rojas-Rivera
authors.forename: R
authors.initials: R
authors.lastname: Armisén
authors.forename: A
authors.initials: A
authors.lastname: Colombo
authors.forename: G
authors.initials: G
authors.lastname: Martínez
authors.forename: A L
authors.initials: AL
authors.lastname: Eguiguren
authors.forename: A
authors.initials: A
authors.lastname: Díaz
authors.forename: S
authors.initials: S
authors.lastname: Kiviluoto
authors.forename: D
authors.initials: D
authors.lastname: Rodríguez
authors.forename: M
authors.initials: M
authors.lastname: Patron
authors.forename: R
authors.initials: R
authors.lastname: Rizzuto
authors.forename: G
authors.initials: G
authors.lastname: Bultynck
authors.forename: M L
authors.initials: ML
authors.lastname: Concha
authors.forename: J
authors.initials: J
authors.lastname: Sierralta
authors.forename: A
authors.initials: A
authors.lastname: Stutzin
authors.forename: C
authors.initials: C
authors.lastname: Hetz
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000235:genetics*; D015027:Zebrafish; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D002118:Calcium; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C570227:Grina protein, mouse; C490015:Tmbim6 protein, mouse