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.
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Abbreviations
- 2-APB:
-
2-aminoethoxydiphenyl borate
- ATF4:
-
activating transcription factor 4
- ATF6:
-
activating transcription factor 6
- BI-1:
-
bax inhibitor 1 protein
- ERAD:
-
endoplasmic reticulum-associated degradation
- Est:
-
estaurosporine
- Eto:
-
etoposide
- GAAP:
-
golgi anti-apoptotic proteín
- GFP:
-
green fluorescent protein
- GHITM:
-
growth-hormone inducible transmembrane protein
- GRINA:
-
glutamate receptor, ionotropic, N-methyl D-asparate-associated protein 1
- HA:
-
human influenza hemagglutinin
- hpf:
-
hours post fertilization
- IP3:
-
inositol 1,4,5-trisphosphate
- IP3-R:
-
inositol 1,4,5-triphosphate receptor
- Mo:
-
morpholine
- shRNA:
-
small hairpin RNA
- Thg:
-
thapsigargin
- Tm:
-
tunicamycin
- TMBIM:
-
transmembrane BAX inhibitor motif-containing
- UPR:
-
unfolded protein response
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Acknowledgements
We apologize to all colleagues whose work could not be cited owing to space limitations. We thank David Ron for providing IRE1α and PERK-deficient cells, Dr. Ann-Hwee Lee for providing and generating IRE1α KO-reconstituted cells, and Dr. NirHacohen and the Broad Institute (Boston, MA, USA) for providing shRNA lentiviral constructs. We also thank Dr. John Reed for kindly providing bi-1−/−cells and Dr. Randal Kaufman for providing ATF6α-deficient cells. We thank Peter Thielen for technical assistant in cloning. We thank Cecilia Zuñigafor for his technical support with fluorescence-activated cell sorting analysis, Tomas Luyten for technical support with 45Ca2+-flux assays and Jan Parys for helpful discussions. This work was supported by the FONDECYT no. 1100176, Alzheimer's Association, Muscular Dystrophy Association, Michael J Fox Foundation for Parkinson Research, North American Spine Society, and ICGEB (to CH); FONDECYT no.1090272 (JS), FONDECYT no. 11090324(AC), Howard Hughes Medical Institute (INTNL 55005940), FONDECYT (1090242) and the Millennium Initiative (ICM P07-048-F) (MC); FONDECYT no. 3100033 (DR); CONICYT Doctoral fellowship (DR-R, GM); UCH-0606 (DR-R); CONICYT no. 24090143 (DR-R), Millennium Nucleus no. P07-048-F (CH, MC, JS); FONDAP Grant no. 15010006 (RA, AS and CH); Grants STRT1/10/044 (GB).
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Rojas-Rivera, D., Armisén, R., Colombo, A. et al. TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis. Cell Death Differ 19, 1013–1026 (2012). https://doi.org/10.1038/cdd.2011.189
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DOI: https://doi.org/10.1038/cdd.2011.189
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