The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.
The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.
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DOI：
10.1073/pnas.2302584120
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发表时间：
2023-05-23
影响因子：
11.1
通讯作者：
Halim, Adnan
中科院分区：
文献类型：
--
作者：
Larsen, Ida Signe Bohse;Povolo, Lorenzo;Zhou, Luping;Tian, Weihua;Mygind, Kasper Johansen;Hintze, John;Jiang, Chen;Hartill, Verity;Prescott, Katrina;Johnson, Colin A.;V. Mullegama, Sureni;McConkie-Rosell, Allyn;McDonald, Marie;Hansen, Lars;Vakhrushev, Sergey Y.;Schjoldager, Katrine T.;Clausen, Henrik;Worzfeld, Thomas;Joshi, Hiren J.;Halim, Adnan
我们证明了TMEM 260基因编码一种新的蛋白特异性O-甘露糖基转移酶，该酶选择性糖基化cMET、罗恩和丛蛋白受体之间共享的共同蛋白结构域。TMEM 260中的双等位基因突变是结构性心脏缺陷和肾异常综合征（SHADs）的基础，SHADs是一种与先天性心脏畸形和幼儿死亡率相关的严重发育障碍。我们发现，致病突变损害了TMEM 260 O-甘露糖基转移酶的功能，这会影响前蛋白的成熟和受体底物的细胞内运输以及上皮的形态发生。我们的研究揭示了高等真核生物中蛋白质O-甘露糖基化的第三种生物合成途径，并将SHR 2鉴定为一种新的先天性糖基化疾病。TMEM 260基因的突变导致结构性心脏缺陷和肾异常综合征，但编码蛋白的功能仍然未知。我们先前报道了在肝细胞生长因子受体（cMET）、巨噬细胞刺激蛋白受体（罗恩）和丛蛋白受体中发现的细胞外免疫球蛋白、丛蛋白、转录因子（IPT）结构域上广泛存在O-甘露聚糖，并进一步证明了由POMT 1/2和跨膜和含四肽重复序列的蛋白1 - 3协调的两种已知的蛋白O-甘露糖基化系统，4个基因家族不需要这些IPT结构域的糖基化。在这里，我们报告说，TMEM 260基因编码的ER定位的蛋白质O-甘露糖基转移酶，选择性糖基化IPT域。我们证明了致病的TMEM 260突变损害IPT结构域的O-甘露糖基化，并且细胞中的TMEM 260敲除导致受体成熟缺陷和3D细胞模型的异常生长。因此，我们的研究确定了哺乳动物中的第三种蛋白质特异性O-甘露糖基化途径，并证明了IPT结构域的O-甘露糖基化在上皮形态发生过程中起着关键作用。我们的研究结果增加了一个新的糖基化途径和基因的先天性糖基化疾病的日益增长的群体。
We demonstrate that the TMEM260 gene encodes a novel protein-specific O-mannosyltransferase that selectively glycosylates a common protein domain shared among cMET, RON, and plexin receptors. Biallelic mutations in TMEM260 underlie structural heart defects and renal anomalies syndrome (SHDRA), a severe developmental disorder associated with congenital cardiac malformations and early childhood mortality. We show that disease-causing mutations impair the TMEM260 O-mannosyltransferase function, which affects proprotein maturation and intracellular trafficking of receptor substrates and epithelial morphogenesis. Our study uncovers a third biosynthetic pathway for protein O-mannosylation in higher eukaryotes and identifies SHDRA as a new congenital disorder of glycosylation. Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.
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影响因子：
2
作者：
Guillen-Ahlers H;Erbe CB;Chevalier FD;Montoya MJ;Zimmerman KD;Langefeld CD;Olivier M;Runge CL
通讯作者：
Runge CL
影响因子：
14.9
作者：
Drula E;Garron ML;Dogan S;Lombard V;Henrissat B;Terrapon N
通讯作者：
Terrapon N
影响因子：
14.9
作者：
Gouw M;Michael S;Sámano-Sánchez H;Kumar M;Zeke A;Lang B;Bely B;Chemes LB;Davey NE;Deng Z;Diella F;Gürth CM;Huber AK;Kleinsorg S;Schlegel LS;Palopoli N;Roey KV;Altenberg B;Reményi A;Dinkel H;Gibson TJ
通讯作者：
Gibson TJ
影响因子：
16.6
作者：
Jiang C;Javed A;Kaiser L;Nava MM;Xu R;Brandt DT;Zhao D;Mayer B;Fernández-Baldovinos J;Zhou L;Höß C;Sawmynaden K;Oleksy A;Matthews D;Weinstein LS;Hahn H;Gröne HJ;Graumann PL;Niessen CM;Offermanns S;Wickström SA;Worzfeld T
通讯作者：
Worzfeld T
影响因子：
5.5
作者：
Eisenhaber B;Sinha S;Jadalanki CK;Shitov VA;Tan QW;Sirota FL;Eisenhaber F
通讯作者：
Eisenhaber F