ZFIN ID: ZDB-PUB-120117-10
TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis
Rojas-Rivera, D., Armisén, R., Colombo, A., Martínez, G., Eguiguren, A.L., Díaz, A., Kiviluoto, S., Rodríguez, D., Patron, M., Rizzuto, R., Bultynck, G., Concha, M.L., Sierralta, J., Stutzin, A., and Hetz, C.
Date: 2012
Source: Cell death and differentiation   19(6): 1013-1026 (Journal)
Registered Authors: Concha, Miguel
Keywords: TMBIM3/GRINA, TMBIM6/BI-1, apoptosis, unfolded protein response, ER stress, calcium signaling
MeSH Terms:
  • Activating Transcription Factor 4/metabolism
  • Animals
  • Apoptosis
  • Calcium/metabolism*
  • Drosophila melanogaster
  • Endoplasmic Reticulum/metabolism*
  • Endoplasmic Reticulum Stress
  • Fibroblasts/metabolism
  • HEK293 Cells
  • HeLa Cells
  • Homeostasis
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors/metabolism
  • Membrane Proteins/antagonists & inhibitors
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Mice
  • Nerve Tissue Proteins/antagonists & inhibitors
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/metabolism*
  • RNA Interference
  • RNA, Small Interfering/metabolism
  • Signal Transduction
  • Unfolded Protein Response/genetics*
  • Zebrafish
  • eIF-2 Kinase/metabolism
PubMed: 22240901 Full text @ Cell Death Differ.
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.