Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects.
Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects.
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DOI：
10.1084/jem.20170453
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发表时间：
2017-12-04
期刊：
影响因子：
--
通讯作者：
Simons M
中科院分区：
文献类型：
--
作者：
Rujano MA;Cannata Serio M;Panasyuk G;Péanne R;Reunert J;Rymen D;Hauser V;Park JH;Freisinger P;Souche E;Guida MC;Maier EM;Wada Y;Jäger S;Krogan NJ;Kretz O;Nobre S;Garcia P;Quelhas D;Bird TD;Raskind WH;Schwake M;Duvet S;Foulquier F;Matthijs G;Marquardt T;Simons M
鲁哈诺等人。报告 ATP6AP2 突变导致肝病、免疫缺陷和精神运动障碍。 ATP6AP2 缺陷会损害 V-ATPase 质子泵的组装和功能，导致蛋白质糖基化和自噬缺陷。多亚基液泡型H+-ATP酶（V-ATP酶）的生物发生在内质网中随着质子孔V0的组装而启动，该组装由一组组装因子控制。在这里，我们在辅助 V-ATP 酶亚基 ATP6AP2（也称为肾素原受体）的胞外域中发现了两个半合子错义突变，这些突变与肝病、免疫缺陷、皮肤松弛和精神运动障碍相关的糖基化障碍有关。我们发现小鼠肝脏中 ATP6AP2 缺陷会导致血清蛋白糖基化低下和自噬缺陷。将其中一种错义突变引入果蝇会导致存活率降低并改变脂质代谢。我们进一步证明，在类肝脂肪体中，自噬失调与溶酶体酸化和哺乳动物雷帕霉素靶点（mTOR）信号传导缺陷相关。最后，两种 ATP6AP2 突变都会损害蛋白质稳定性以及与 ATP6AP1（V0 组装复合体成员）的相互作用。总的来说，我们的数据表明 ATP6AP2 的错义突变导致 V-ATP 酶组装受损以及随后的糖基化和自噬缺陷。
Rujano et al. report mutations in ATP6AP2 leading to liver disease, immunodeficiency, and psychomotor impairment. ATP6AP2 deficiency impairs the assembly and function of the V-ATPase proton pump, causing defects in protein glycosylation and autophagy. The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy.
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影响因子：
3.5
作者：
Dubos A;Castells-Nobau A;Meziane H;Oortveld MA;Houbaert X;Iacono G;Martin C;Mittelhaeuser C;Lalanne V;Kramer JM;Bhukel A;Quentin C;Slabbert J;Verstreken P;Sigrist SJ;Messaddeq N;Birling MC;Selloum M;Stunnenberg HG;Humeau Y;Schenck A;Herault Y
通讯作者：
Herault Y
影响因子：
8.3
作者：
Cousin, Christelle;Bracquart, Diane;Nguyen, Genevieve
通讯作者：
Nguyen, Genevieve
影响因子：
13.3
作者：
Kissing, Sandra;Rudnik, Soenke;Saftig, Paul
通讯作者：
Saftig, Paul
影响因子：
3.4
作者：
Faid, Valegh;Chirat, Frederic;Morelle, Willy
通讯作者：
Morelle, Willy
影响因子：
30.8
作者：
Kortuem, Fanny;Caputo, Viviana;Kutsche, Kerstin
通讯作者：
Kutsche, Kerstin