Yan Ye, Wladyka Cynthia, Fujii Junichi, Sockanathan Shanthini
The Solomon Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, PCTB1004, 725 N Wolfe Street, Baltimore, Maryland 21205, USA.
Department of Biochemistry and Molecular Biology, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan.
Nat Commun. 2015 May 6;6:7006. doi: 10.1038/ncomms8006.
Neural progenitors and terminally differentiated neurons show distinct redox profiles, suggesting that coupled-redox cascades regulate the initiation and progression of neuronal differentiation. Discrete cellular compartments have different redox environments and how they contribute to differentiation is unclear. Here we show that Prdx4, an endoplasmic reticulum (ER) enzyme that metabolizes H2O2, acts as a tunable regulator of neurogenesis via its compartmentalized thiol-oxidative function. Prdx4 ablation causes premature motor neuron differentiation and progenitor depletion, leading to imbalances in subtype-specific motor neurons. GDE2, a six-transmembrane protein that induces differentiation by downregulating Notch signalling through surface cleavage of GPI-anchored proteins, is targeted by Prdx4 oxidative activity. Prdx4 dimers generated by H2O2 metabolism oxidize two cysteine residues within the GDE2 enzymatic domain, which blocks GDE2 trafficking to the plasma membrane and prevents GDE2 neurogeneic function. Thus, Prdx4 oxidative activity acts as a sensor to directly couple neuronal differentiation with redox environments in the ER.
神经祖细胞和终末分化神经元表现出不同的氧化还原特征，这表明耦合氧化还原级联反应调节神经元分化的起始和进程。离散的细胞区室具有不同的氧化还原环境，而它们如何促进分化尚不清楚。在这里，我们表明，内质网（ER）中代谢过氧化氢的酶Prdx4通过其区域化的硫醇氧化功能，作为神经发生的可调谐调节器。Prdx4缺失会导致运动神经元过早分化和祖细胞耗竭，导致亚型特异性运动神经元失衡。GDE2是一种六跨膜蛋白，通过对糖基磷脂酰肌醇锚定蛋白的表面切割来下调Notch信号传导从而诱导分化，它是Prdx4氧化活性的靶点。由过氧化氢代谢产生的Prdx4二聚体氧化GDE2酶结构域内的两个半胱氨酸残基，这会阻止GDE2转运到质膜并阻止GDE2的神经发生功能。因此，Prdx4氧化活性作为一种传感器，直接将神经元分化与内质网中的氧化还原环境联系起来。
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