The EGF repeat-specific O-GlcNAc-transferase Eogt interacts with notch signaling and pyrimidine metabolism pathways in Drosophila.
The EGF repeat-specific O-GlcNAc-transferase Eogt interacts with notch signaling and pyrimidine metabolism pathways in Drosophila.
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DOI：
10.1371/journal.pone.0062835
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Stanley P
中科院分区：
文献类型：
--
作者：
Müller R;Jenny A;Stanley P
O-GlcNAc转移酶Eogt在包括Dump和Notch在内的分泌途径中修改蛋白质中的EGF重复序列。在本文中，我们发现Notch配体Delta和Serrate也是Eogt的底物，UDP-GlcNAc结合DXD基序的突变极大地降低了酶的活性，Eogt和细胞质O-GlcNAc转移酶OGT在果蝇幼虫中具有不同的底物。Eogt的缺失对幼虫是致命的，会扰乱矮胖功能，但不会明显扰乱Notch信号。为了确定与eogt的新的遗传互作，我们研究了eogt基因敲除导致的翼泡形成的显性修饰。出乎意料的是，典型的Notch信号通路的几个成员的杂合性抑制了翼泡的形成。重要的是，在嘧啶代谢过程中与突变体之间存在广泛的遗传相互作用。去除嘧啶合成等位基因抑制了翼泡的形成，而去除尿嘧啶分解代谢等位基因则是具有eogt击倒的合成致死作用。因此，Eogt可能通过O-GlcNAc修饰其EGF重复序列来调节蛋白质的功能，并通过影响嘧啶的合成和分解代谢来调节细胞代谢。我们认为，eogt在翅膀上的敲击导致代谢和信号扰动，从而增加胞浆尿嘧啶水平，从而导致翅膀水泡的形成。
The O-GlcNAc transferase Eogt modifies EGF repeats in proteins that transit the secretory pathway, including Dumpy and Notch. In this paper, we show that the Notch ligands Delta and Serrate are also substrates of Eogt, that mutation of a putative UDP-GlcNAc binding DXD motif greatly reduces enzyme activity, and that Eogt and the cytoplasmic O-GlcNAc transferase Ogt have distinct substrates in Drosophila larvae. Loss of Eogt is larval lethal and disrupts Dumpy functions, but does not obviously perturb Notch signaling. To identify novel genetic interactions with eogt, we investigated dominant modification of wing blister formation caused by knock-down of eogt. Unexpectedly, heterozygosity for several members of the canonical Notch signaling pathway suppressed wing blister formation. And importantly, extensive genetic interactions with mutants in pyrimidine metabolism were identified. Removal of pyrimidine synthesis alleles suppressed wing blister formation, while removal of uracil catabolism alleles was synthetic lethal with eogt knock-down. Therefore, Eogt may regulate protein functions by O-GlcNAc modification of their EGF repeats, and cellular metabolism by affecting pyrimidine synthesis and catabolism. We propose that eogt knock-down in the wing leads to metabolic and signaling perturbations that increase cytosolic uracil levels, thereby causing wing blister formation.
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影响因子：
7.7
作者：
Herranz, H;Stamataki, E;Milán, M
通讯作者：
Milán, M
DOI：
10.1073/pnas.1200425109
发表时间：
2012-05-08
影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
4.3
作者：
Ise, Hirohiko;Kobayashi, Satoshi;Akaike, Toshihiro
通讯作者：
Akaike, Toshihiro