D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function
D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function
复制标题
DOI：
10.1101/gad.198200.112
复制
发表时间：
2012-09-15
影响因子：
10.5
通讯作者：
Mak, Tak Wah
中科院分区：
文献类型：
--
作者：
Sasaki, Masato;Knobbe, Christiane B.;Mak, Tak Wah
异柠檬酸脱氢酶-1 (IDH1) R132 突变发生在神经胶质瘤中，但其生理意义尚不清楚。在这里，我们描述了大脑特异性 Idh1 R132H 条件敲入 (KI) 小鼠的产生和表征。 Idh1 突变会导致出血和围产期死亡。令人惊讶的是，尽管 NADP(+)/NADPH 比率明显增加，但 Idh1-KI 脑细胞中的细胞内活性氧 (ROS) 却减弱。 Idh1-KI 细胞还表现出高水平的 D-2-羟基戊二酸 (D2HG)，这与缺氧诱导转录因子 1 α (Hif1 α) 的脯氨酰羟基化受到抑制以及 Hif1a 靶基因转录上调有关。有趣的是，D2HG 还能阻断胶原蛋白的脯氨酰羟基化，从而导致胶原蛋白成熟缺陷。由未成熟胶原蛋白积累引起的内质网（ER）应激反应可能是这些突变体胚胎致死的原因。重要的是，D2HG 介导的胶原蛋白成熟受损也会导致基底膜 (BM) 畸变，这可能在神经胶质瘤的进展中发挥作用。我们的研究提供了强有力的体内证据，证明突变型 Idh1 酶产生的 D2HG 是造成上述效应的原因。
Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knockin (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP(+)/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1 alpha (Hif1 alpha) and up-regulated Hif1a target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.