Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid β-oxidation
Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid β-oxidation
复制标题
DOI：
10.1073/pnas.1910765117
复制
发表时间：
2020-02-04
影响因子：
11.1
通讯作者：
Zhang，Jiyan
中科院分区：
文献类型：
--
作者：
Zhang，Xueying;Zhang，Yao-Lin;Zhang，Jiyan
类泛素化是一种泛素化途径，通过将NEDD8与特定底物蛋白中的赖氨酸共价偶联来控制细胞的存活和增殖。然而，类化修饰在哺乳动物代谢中的生理作用仍然难以捉摸，并且没有确定线粒体靶点。在这里，我们报道了肝脏特异性缺乏NEDD8或泛素样修饰物激活酶3 (UBA3) （NEDD8激活酶的催化亚基）的小鼠模型，表现出自发性脂肪肝新生儿死亡以及肝细胞衰老。特别是肝脏特异性UBA3缺乏会导致类似于II型戊二酸尿症（GA-II）的全体性异常，这是一种罕见的常染色体隐性遗传脂肪酸氧化障碍，由线粒体电子转移黄蛋白（ETFA和ETFB）或相应的泛醌氧化还原酶缺陷引起。各种策略抑制类泛素化导致新生儿肝脏和胚胎肝细胞中ETFs蛋白水平下降。肝类化修饰也能增强成年小鼠的ETF表达，防止禁食引起的脂肪变性和死亡。有趣的是，类化修饰在肝脏线粒体中是活跃的。etf是类黄酮化底物，类黄酮化通过抑制其泛素化和降解来稳定etf。此外，在GA-II患者中发现的某些ETFs突变阻碍了这些底物的类化修饰。综上所述，我们的结果揭示了类黄酮化的底物，并增加了对GA-II的了解。
Neddylation is a ubiquitination-like pathway that controls cell survival and proliferation by covalently conjugating NEDD8 to lysines in specific substrate proteins. However, the physiological role of neddylation in mammalian metabolism remains elusive, and no mitochondrial targets have been identified. Here, we report that mouse models with liver-specific deficiency of NEDD8 or ubiquitin-like modifier activating enzyme 3 (UBA3), the catalytic subunit of the NEDD8-activating enzyme, exhibit neonatal death with spontaneous fatty liver as well as hepatic cellular senescence. In particular, liver-specific UBA3 deficiency leads to systemic abnormalities similar to glutaric aciduria type II (GA-II), a rare autosomal recessive inherited fatty acid oxidation disorder resulting from defects in mitochondrial electron transfer flavoproteins (ETFs: ETFA and ETFB) or the corresponding ubiquinone oxidoreductase. Neddylation inhibition by various strategies results in decreased protein levels of ETFs in neonatal livers and embryonic hepatocytes. Hepatic neddylation also enhances ETF expression in adult mice and prevents fasting-induced steatosis and mortality. Interestingly, neddylation is active in hepatic mitochondria. ETFs are neddylation substrates, and neddylation stabilizes ETFs by inhibiting their ubiquitination and degradation. Moreover, certain mutations of ETFs found in GA-II patients hinder the neddylation of these substrates. Taken together, our results reveal substrates for neddylation and add insight into GA-II.