PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD.
PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD.
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PDIA3通过STAT3信号传导抑制脑内皮细胞和秀丽隐杆线虫的线粒体呼吸功能，并降低OGD后的存活率。
DOI：
10.1186/s12964-021-00794-z
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发表时间：
2021-12-18
期刊：
影响因子：
--
通讯作者：
Hagg T
中科院分区：
文献类型：
--
作者：
Keasey MP;Razskazovskiy V;Jia C;Peterknecht ED;Bradshaw PC;Hagg T
蛋白二硫异构酶A3 （PDIA3，也称为GRP58， ER-60, ERp57）在物种中是保守的，介导内质网中的蛋白质折叠。据报道，PDIA3是STAT3的伴侣。然而，PDIA3在调节线粒体生物能量学和STAT3丝氨酸727 （S727）磷酸化中的作用尚未被描述。比较了永生化人脑微血管细胞（CMEC）野生型或PDIA3为零，全生物秀丽隐杆线虫（C. Elegans）野生型或pdi3（蠕虫同源物）为零的线粒体呼吸作用。观察PDIA3-/-和WT细胞的线粒体形态和细胞信号通路。对PDIA3-/-细胞进行氧糖剥夺（OGD），观察PDIA3对损伤后细胞存活的影响。我们发现，在培养的cmec中使用CRISPR-Cas9删除PDIA3基因导致线粒体生物能量功能增加。在秀丽隐杆线虫中，基因缺失或RNAi敲低pdi-3也增加了呼吸频率，证实了该基因在调节线粒体生物能量学中的保守作用。在培养的PDIA3-/- cmes中，过表达WT PDIA3可逆转PDIA3-/-生物能表型。PDIA3-/-和siRNA敲低导致STAT3的S727残基磷酸化增加，已知其促进线粒体生物能量功能。STAT3抑制剂可逆转PDIA3-/- cmec的呼吸增加。在PDIA3-/- cmec中，线粒体膜电位和活性氧产生增加，但线粒体质量没有增加，表明线粒体生物能量能力增加。最后，PDIA3-/- cmec对氧葡萄糖剥夺的抵抗力更强，而STAT3的抑制降低了保护作用。我们发现PDIA3通过抑制stat3s727磷酸化抑制线粒体生物能量功能的新作用。在线版本包含补充材料，可在10.1186/s12964-021-00794-z获得。
Protein disulfide isomerase A3 (PDIA3, also named GRP58, ER-60, ERp57) is conserved across species and mediates protein folding in the endoplasmic reticulum. PDIA3 is, reportedly, a chaperone for STAT3. However, the role of PDIA3 in regulating mitochondrial bioenergetics and STAT3 phosphorylation at serine 727 (S727) has not been described. Mitochondrial respiration was compared in immortalized human cerebral microvascular cells (CMEC) wild type or null for PDIA3 and in whole organism C. Elegans WT or null for pdi-3 (worm homologue). Mitochondrial morphology and cell signaling pathways in PDIA3-/- and WT cells were assessed. PDIA3-/- cells were subjected to oxygen–glucose deprivation (OGD) to determine the effects of PDIA3 on cell survival after injury. We show that PDIA3 gene deletion using CRISPR-Cas9 in cultured CMECs leads to an increase in mitochondrial bioenergetic function. In C. elegans, gene deletion or RNAi knockdown of pdi-3 also increased respiratory rates, confirming a conserved role for this gene in regulating mitochondrial bioenergetics. The PDIA3-/- bioenergetic phenotype was reversed by overexpression of WT PDIA3 in cultured PDIA3-/- CMECs. PDIA3-/- and siRNA knockdown caused an increase in phosphorylation of the S727 residue of STAT3, which is known to promote mitochondrial bioenergetic function. Increased respiration in PDIA3-/- CMECs was reversed by a STAT3 inhibitor. In PDIA3-/- CMECs, mitochondrial membrane potential and reactive oxygen species production, but not mitochondrial mass, was increased, suggesting an increased mitochondrial bioenergetic capacity. Finally, PDIA3-/- CMECs were more resistant to oxygen–glucose deprivation, while STAT3 inhibition reduced the protective effect. We have discovered a novel role for PDIA3 in suppressing mitochondrial bioenergetic function by inhibiting STAT3 S727 phosphorylation. The online version contains supplementary material available at 10.1186/s12964-021-00794-z.
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影响因子：
3.3
作者：
Burniston JG;Kenyani J;Gray D;Guadagnin E;Jarman IH;Cobley JN;Cuthbertson DJ;Chen YW;Wastling JM;Lisboa PJ;Koch LG;Britton SL
通讯作者：
Britton SL
影响因子：
8.3
作者：
Doll DN;Hu H;Sun J;Lewis SE;Simpkins JW;Ren X
通讯作者：
Ren X
影响因子：
9.5
作者：
Boengler K;Hilfiker-Kleiner D;Heusch G;Schulz R
通讯作者：
Schulz R
影响因子：
4.8
作者：
Banerjee K;Keasey MP;Razskazovskiy V;Visavadiya NP;Jia C;Hagg T
通讯作者：
Hagg T
影响因子：
3.7
作者：
Edwards CB;Copes N;Brito AG;Canfield J;Bradshaw PC
通讯作者：
Bradshaw PC