Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells.
Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells.
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DOI：
10.1016/j.cellsig.2017.05.007
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发表时间：
2017-08
影响因子：
4.8
通讯作者：
Hagg T
中科院分区：
文献类型：
--
作者：
Banerjee K;Keasey MP;Razskazovskiy V;Visavadiya NP;Jia C;Hagg T
内质网（ER）应激过度会导致许多疾病中的细胞损失，例如，导致脊髓损伤后内皮细胞损失。在此，我们确定内质网应激诱导的线粒体功能障碍是否可由我们最近发现的粘着斑激酶（FAK） - 线粒体STAT3通路的中断来解释。内质网应激通过毒胡萝卜素或衣霉素在脑源性小鼠bEnd5内皮细胞中诱导，并在72小时内导致细胞凋亡。同时，内质网应激导致线粒体功能障碍，表现为生物能量功能降低、线粒体膜电位丧失和线粒体自噬增加。内质网应激导致线粒体磷酸化S727 - STAT3减少，已知其对维持线粒体功能很重要。上游细胞质FAK的正常激活或磷酸化也减少，其机制涉及酪氨酸磷酸酶和钙信号，如分别由药物抑制剂双过氧钒（bpV）和2 - 氨基乙氧基二苯硼烷（APB）所示。APB减轻了FAK和STAT3磷酸化的减少，并改善了内质网应激导致的内皮细胞存活。使用CRISPR技术将细胞转染为STAT3缺失并用STAT3突变体证实了S727 - STAT3抑制在内质网应激介导的细胞损失中的特定作用。这些数据表明，内质网应激期间FAK信号的丧失通过降低线粒体STAT3的保护作用导致线粒体功能障碍，从而导致内皮细胞死亡。我们提出刺激FAK - STAT3通路是针对病理性内质网应激的一种新的治疗方法。
提出的FAK - STAT通路在内质网应激中的作用。在生理条件下，整合素信号效应物FAK促进S727 - STAT3的磷酸化，这导致其线粒体转位，促进线粒体生物能量学和完整性以及细胞存活。由衣霉素（TM）或毒胡萝卜素（TG）诱导的内质网应激通过蛋白酪氨酸磷酸酶（PTP）活性（被bpV阻断）或高钙水平（被APB阻断）降低pFAK，导致线粒体pS727 - STAT3减少和随后的功能障碍。
Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72 h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy. ER stress caused a reduction in mitochondrial phosphorylated S727-STAT3, known to be important for maintaining mitochondrial function. Normal activation or phosphorylation of the upstream cytoplasmic FAK was also reduced, through mechanisms that involve tyrosine phosphatases and calcium signaling, as shown by pharmacological inhibitors, bisperoxovanadium (bpV) and 2-aminoethoxydiphenylborane (APB), respectively. APB mitigated the reduction in FAK and STAT3 phosphorylation, and improved endothelial cell survival caused by ER stress. Transfection of cells rendered null for STAT3 using CRISPR technology with STAT3 mutants confirmed the specific involvement of S727-STAT3 inhibition in ER stress-mediated cell loss. These data suggest that loss of FAK signaling during ER stress causes mitochondrial dysfunction by reducing the protective effects of mitochondrial STAT3, leading to endothelial cell death. We propose that stimulation of the FAK-STAT3 pathway is a novel therapeutic approach against pathological ER stress. Proposed FAK-STAT pathway involvement in ER stress. Under physiological conditions, the integrin signaling effector FAK promotes phosphorylation of S727-STAT3 which leads to its mitochondrial translocation to promote mitochondrial bioenergetics and integrity, and cell survival. ER stress induced by TM or TG decreases pFAK through protein tyrosine phosphatase (PTP) activity (blocked by bpV) or high calcium levels (blocked by APB), leading to decreased mitochondrial pS727-STAT3 and subsequent dysfunction.
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影响因子：
64.5
作者：
Jan, YW;Matter, M;Ruoslahti, E
通讯作者：
Ruoslahti, E
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：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
通讯作者：
O'Riordan MX
影响因子：
14.5
作者：
Han, Shu;Arnold, Sheila A.;Hagg, Theo
通讯作者：
Hagg, Theo
影响因子：
3.1
作者：
Boengler, Kerstin;Ungefug, Elvira;Schulz, Rainer
通讯作者：
Schulz, Rainer