TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo
TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo
复制标题
TRAF6 介导的 SM22 α K21 泛素化促进 G6PD 激活和 NADPH 产生，有助于体外和体内 GSH 稳态和 VSMC 存活
DOI：
10.1161/circresaha.115.306233
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发表时间：
2015-09-25
影响因子：
20.1
通讯作者：
Han, Mei
中科院分区：
文献类型：
--
作者：
Dong, Li-Hua;Li, Liang;Han, Mei
理由：血管平滑肌细胞（VSMC）在应激条件下的存活对于促进血管修复是不可或缺的，但在动脉粥样硬化的发展过程中促进了斑块的稳定。细胞骨架相关平滑肌（SM） 22蛋白参与VSMC表型的调节，而戊糖磷酸途径通过产生二氢烟酰胺腺嘌呤二核苷酸磷酸在细胞增殖中起重要作用。目的：探讨血管疾病发生发展过程中二氢烟酰胺腺嘌呤二核苷酸磷酸生成与SM22活性的关系。方法和结果：我们发现葡萄糖-6-磷酸脱氢酶（G6PD）的表达和活性在血小板衍生生长因子(PDGF)- bb诱导的增生性VSMCs中得到促进。PDGF-BB以SM22 K21泛素化依赖的方式诱导G6PD膜易位和激活。具体来说，泛素化的SM22与G6PD相互作用并介导G6PD膜易位。此外，我们发现肿瘤坏死因子受体相关因子（TRAF） 6在PDGF-BB刺激中以k63连锁的方式介导SM22 K21泛素化。TRAF6的敲低降低了细胞膜易位和G6PD的活性，同时降低了SM22 K21的泛素化。PDGF-BB诱导激活的G6PD水平升高，通过刺激戊糖磷酸途径导致二氢烟酰胺腺嘌呤二核苷酸磷酸生成增加，从而通过谷胱甘肽内稳态提高体内和体外VSMC活力，减少细胞凋亡。结论：我们提供的证据表明，traf6诱导的SM22泛素化通过增加G6PD活性和二氢烟酰胺腺嘌呤二核苷酸磷酸的产生来维持VSMC的生存。TRAF6-SM22-G6PD通路是糖代谢与VSMC存活相关的新机制，有利于损伤后血管修复，但有利于动脉粥样硬化斑块的稳定。
Rationale: Vascular smooth muscle cell (VSMC) survival under stressful conditions is integral to promoting vascular repair, but facilitates plaque stability during the development of atherosclerosis. The cytoskeleton-associated smooth muscle (SM) 22 protein is involved in the regulation of VSMC phenotypes, whereas the pentose phosphate pathway plays an essential role in cell proliferation through the production of dihydronicotinamide adenine dinucleotide phosphate.Objective: To identify the relationship between dihydronicotinamide adenine dinucleotide phosphate production and SM22 activity in the development and progression of vascular diseases.Methods and Results: We showed that the expression and activity of glucose-6-phosphate dehydrogenase (G6PD) are promoted in platelet-derived growth factor (PDGF)-BB-induced proliferative VSMCs. PDGF-BB induced G6PD membrane translocation and activation in an SM22 K21 ubiquitination-dependent manner. Specifically, the ubiquitinated SM22 interacted with G6PD and mediated G6PD membrane translocation. Furthermore, we found that tumor necrosis factor receptor-associated factor (TRAF) 6 mediated SM22 K21 ubiquitination in a K63-linked manner on PDGF-BB stimulation. Knockdown of TRAF6 decreased the membrane translocation and activity of G6PD, in parallel with reduced SM22 K21 ubiquitination. Elevated levels of activated G6PD consequent to PDGF-BB induction led to increased dihydronicotinamide adenine dinucleotide phosphate generation through stimulation of the pentose phosphate pathway, which enhanced VSMC viability and reduced apoptosis in vivo and in vitro via glutathione homeostasis.Conclusions: We provide evidence that TRAF6-induced SM22 ubiquitination maintains VSMC survival through increased G6PD activity and dihydronicotinamide adenine dinucleotide phosphate production. The TRAF6-SM22-G6PD pathway is a novel mechanism underlying the association between glucose metabolism and VSMC survival, which is beneficial for vascular repair after injury but facilitates atherosclerotic plaque stability.