|ZFIN ID: ZDB-PUB-190608-6|
Deficiency in the membrane protein Tmbim3a/Grinaa initiates cold-induced ER stress and cell death by activating an intrinsic apoptotic pathway in zebrafish
Chen, K., Li, X., Song, G., Zhou, T., Long, Y., Li, Q., Zhong, S., Cui, Z.
|Source:||The Journal of biological chemistry 294(30): 11445-11457 (Journal)|
|Registered Authors:||Chen, Kai, Cui, Zongbin, Li, Qing, Li, Xixi, Long, Yong, Song, Guili|
|Keywords:||Apoptosis, Calcium homeostasis, Cold exposure, Grinaa, apoptosis, calcium intracellular release, endoplasmic reticulum stress (ER stress), endoplasmic reticulum stress; Calcium homeostasis, stress response, zebrafish|
|PubMed:||31171717 Full text @ J. Biol. Chem.|
Chen, K., Li, X., Song, G., Zhou, T., Long, Y., Li, Q., Zhong, S., Cui, Z. (2019) Deficiency in the membrane protein Tmbim3a/Grinaa initiates cold-induced ER stress and cell death by activating an intrinsic apoptotic pathway in zebrafish. The Journal of biological chemistry. 294(30):11445-11457.
ABSTRACTMost members of the family of proteins containing a transmembrane BAX inhibitor motif (TMBIM) have anti-apoptotic activity, but their in vivo functions and intracellular mechanisms remain obscure. Here, we report that zebrafish Tmbim3a/Grinaa functions in the prevention of cold-induced endoplasmic reticulum (ER) stress and apoptosis. Using a gene-trapping approach, we obtained a mutant zebrafish line in which the expression of the tmbim3a/grinaa gene is disrupted by a Tol2 transposon insertion. Homozygous tmbim3a/grinaa mutant larvae exhibited time-dependently increased mortality and apoptosis under cold exposure (at 16ºC). Mechanistically, using immunofluorescence, fluorescence-based assessments of intracellular/mitochondrial Ca²+ levels, mitochondrial membrane potential measurements, and Ca²+-ATPase assays, we found that cold exposure suppresses sarcoplasmic/ER Ca²+-ATPase (SERCA) activity and induces the unfolded protein response (UPR) and ER stress. We also found that the cold-induced ER stress is increased in homozygous tmbim3a/grinaa mutant embryos. The cold-stress hyper-sensitivity of the tmbim3a/grinaa mutants was tightly associated with disrupted intracellular Ca²+ homeostasis, followed by mitochondrial Ca²+ overload and cytochrome c release, leading to the activation of caspase 9- and caspase 3-mediated intrinsic apoptotic pathways. Treatment of zebrafish larvae with the intracellular Ca²+ chelator BAPTA-AM or with 2-APB, an inhibitor of the calcium-releasing protein IP3 receptor (IP3R), alleviated cold-induced cell death. Together, these findings unveil a key role of Tmbim3a/Grinaa in relieving cold-induced ER stress and in protecting cells against caspase 9- and 3-mediated apoptosis during zebrafish development.