Etoposide-induced protein 2.4 functions as a regulator of the calcium ATPase and protects pancreatic -cell survival
Etoposide-induced protein 2.4 functions as a regulator of the calcium ATPase and protects pancreatic -cell survival
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依托泊苷诱导蛋白 2.4 作为钙 ATP 酶调节剂发挥作用并保护胰腺细胞存活
DOI：
10.1074/jbc.ra118.002399
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发表时间：
2018
影响因子：
4.8
通讯作者：
Xu Pingyong
中科院分区：
文献类型：
--
作者：
Yuan Lin;Wang Huiyu;Liu Qi;Wang Zhe;Zhang Mingshu;Zhao Yan;Liang Kuo;Chen Liangyi;Xu Tao;Xu Pingyong
钙稳态对于维持胰腺β细胞的活性和功能是必不可少的，并且在预防糖尿病的发展中起着关键作用。β细胞的主要钙泵--肌浆/内质网钙转运蛋白2(ATP2a2)水平降低，常见于糖尿病患者和糖尿病动物模型。然而，ATP2a2的调节因子和调控ATP2a2活性的分子机制仍不清楚。依托泊苷诱导蛋白2.4(EI24)也在糖尿病患者的β细胞中下调，但EI24水平降低对β细胞功能的影响尚不清楚。在这里，使用Cre-loxP和基于CRISPR/Cas9的基因组敲除(KO)方法来产生胰腺β细胞特异性的Ei24KO小鼠和胰腺β细胞系，我们发现Ei24调节ATP2a2的活性。具体地说，我们观察到Ei24通过Ei24残基293-299与ATP2a2结合，我们在这里将其命名为ATP2a2相互作用区(AIR)。Ei24的缺失使ATP2a2失活，扰乱钙稳态，并使钙/钙调蛋白依赖的蛋白激酶2(CAMKK2)-AMP激活的蛋白激酶(AMPK)途径失活。内质网钙浓度的升高或激动剂诱导的AMPK激活挽救了Ei24KO小鼠胰腺β细胞的存活并改善了糖耐量。我们的发现表明，靶向Ei24-ATP2a2相互作用以增加ATP2a2活性可以保护糖尿病模型中的胰腺β细胞，改善血糖稳态，提示Ei24可能成为预防或管理糖尿病的靶点。
Calcium homeostasis is essential for maintaining the viability and function of pancreatic β cells and plays a key role in preventing the development of diabetes. Decreased levels of ATPase sarcoplasmic/endoplasmic reticulum Ca2+-transporting 2 (ATP2a2), the main calcium pump in β cells, are often found in individuals with diabetes and in diabetic animal models. However, the regulators of ATP2a2 and the molecular mechanisms responsible for controlling ATP2a2 activity remain unclear. Etoposide-induced protein 2.4 (Ei24) is also down-regulated in β cells of diabetic individuals, whereas the effect of decreased Ei24 level on β-cell function is not clarified. Here, using Cre-LoxP and CRISPR/Cas9-based genomic knockout (KO) approaches to generate pancreatic β cell–specificEi24KO mice and pancreatic β-cell lines, we found that Ei24 regulates ATP2a2 activity. Specifically, we observed that Ei24 binds to ATP2a2 through Ei24 residues 293–299, which we named here the ATP2a2-interacting region (AIR). Loss of Ei24 inactivated ATP2a2, disrupted calcium homeostasis, and deactivated the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)–AMP-activated protein kinase (AMPK) pathway. Elevation of calcium concentration in the endoplasmic reticulum or agonist-induced AMPK activation rescued pancreatic β-cell survival and improved glucose tolerance ofEi24KO mice. Our findings indicate that targeting the Ei24–ATP2a2 interaction to increase ATP2a2 activity can protect pancreatic β cells and improve glucose homeostasis in diabetic models, suggesting that Ei24 could potentially serve as a target to prevent or manage diabetes.