Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function
Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function
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小鼠胰腺 β 细胞中 E2 SUMO 结合酶 (UBC9) 的条件消融和过度表达都会导致 β 细胞功能受损。
DOI：
10.1007/s00125-017-4523-9
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发表时间：
2018-04-01
期刊：
影响因子：
8.2
通讯作者：
Wang, Cong-Yi
中科院分区：
文献类型：
--
作者：
He, Xiaoyu;Lai, Qiaohong;Wang, Cong-Yi
目的/假设小泛素样修饰物（SUMO）翻译后连接到靶蛋白的赖氨酸（K）残基（SUMO化）是进化上保守的调节机制。这种修饰先前已被证明与细胞过程的一种非常通用的调节机制的控制有关。然而，E2 SUMO结合酶（UBC 9）介导的SUMO化功能在胰腺β cells.Methods诱导β细胞特异性Ubc 9（也称为Ube 2 i）敲除（KO; Ubc 9（Delta β））和转基因（Ubc 9（Tg））小鼠的确切调控作用和生物学作用，以解决SUMO化对β细胞活力和功能的影响。在8周龄时使用他莫昔芬诱导ubc 9缺陷或过度表达。为了研究所涉及的机制，我们仔细研究了转录因子核因子红细胞2相关因子2（NRF 2）通过SUMO化在β cells.Results诱导Ubc 9缺陷后，Ubc 9（Delta β）胰岛显示出活性氧（ROS）的积累比Ubc 9（f/f）控制胰岛高3.5倍。来自Ubc 9（Delta beta）小鼠的胰岛在他莫昔芬治疗后也具有胰岛素含量降低和β细胞质量损失。具体而言，在Ubc 9缺失后第45天，Ubc 9（Delta beta）小鼠中仅保留40%的β细胞质量，而到第75天，90%的β细胞质量丢失。在诱导Ubc 9缺陷后8周，在一些Ubc 9（Delta beta）小鼠中注意到糖尿病发作，并且在他莫昔芬治疗后10周，所有小鼠都发展为糖尿病。相比之下，Ubc 9（Tg）β细胞显示出增加的抗氧化能力，但胰岛素分泌受损。与自发发展糖尿病的Ubc 9（Delta beta）小鼠不同，Ubc 9（Tg）小鼠保持正常的非空腹血糖水平而不发展糖尿病。有人指出，SUMO化的NRF 2促进其核表达沿着增强的转录活性，从而防止ROS在β cells.Conclusions/interpretation中的积累SUMO化功能是必需的，以防止氧化应激在β细胞中，这种机制是，至少在部分，通过调节NRF 2的活性，以提高ROS解毒。稳态SUMO化也可能是维持β细胞功能所必需的。
Aims/hypothesis Post-translational attachment of a small ubiquitin-like modifier (SUMO) to the lysine (K) residue(s) of target proteins (SUMOylation) is an evolutionary conserved regulatory mechanism. This modification has previously been demonstrated to be implicated in the control of a remarkably versatile regulatory mechanism of cellular processes. However, the exact regulatory role and biological actions of the E2 SUMO-conjugating enzyme (UBC9)-mediated SUMOylation function in pancreatic beta cells has remained elusive.Methods Inducible beta cell-specific Ubc9 (also known as Ube2i) knockout (KO; Ubc9(Delta beta)) and transgenic (Ubc9(Tg)) mice were employed to address the impact of SUMOylation on beta cell viability and functionality. Ubc9 deficiency or overexpression was induced at 8 weeks of age using tamoxifen. To study the mechanism involved, we closely examined the regulation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) through SUMOylation in beta cells.Results Upon induction of Ubc9 deficiency, Ubc9(Delta beta) islets exhibited a 3.5-fold higher accumulation of reactive oxygen species (ROS) than Ubc9(f/f) control islets. Islets from Ubc9(Delta beta) mice also had decreased insulin content and loss of beta cell mass after tamoxifen treatment. Specifically, at day 45 after Ubc9 deletion only 40% of beta cell mass remained in Ubc9(Delta beta) mice, while 90% of beta cell mass was lost by day 75. Diabetes onset was noted in some Ubc9(Delta beta) mice 8weeks after induction of Ubc9 deficiency and all mice developed diabetes by 10 weeks following tamoxifen treatment. In contrast, Ubc9(Tg) beta cells displayed an increased antioxidant ability but impaired insulin secretion. Unlike Ubc9(Delta beta) mice, which spontaneously developed diabetes, Ubc9(Tg) mice preserved normal non-fasting blood glucose levels without developing diabetes. It was noted that SUMOylation of NRF2 promoted its nuclear expression along with enhanced transcriptional activity, thereby preventing ROS accumulation in beta cells.Conclusions/interpretation SUMOylation function is required to protect against oxidative stress in beta cells; this mechanism is, at least in part, carried out by the regulation of NRF2 activity to enhance ROS detoxification. Homeostatic SUMOylation is also likely to be essential for maintaining beta cell functionality.