Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Earnest J. P. Daniel, Andrew C. Edmondson, Yair Argon, Hind Alsharhan, Christina Lam, Hudson H. Freeze, Miao He
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Abstract

ALG3-CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol-P-Man to Dol-PP-Man5GlcNAc2 (Man5) forming Dol-PP-Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3-CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway. In addition, we show that N-linked Man3-4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non-hepatic origin. We found that like other CDGs such as ALG1- or PMM2-CDG, in transferrin, the assembling intermediate Man5 in ALG3-CDG, are likely further processed into a distinct glycan, NeuAc1Gal1GlcNAc1Man3GlcNAc2, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono-antennary glycan with the same molecular weight as the truncated glycan described in MGAT2-CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3-CDG which will have important implications in the pathogenesis of CDG.

ALG3-CDG 的糖延伸缺陷和内质网压力
ALG3-CDG是一种罕见的先天性糖基化紊乱(CDG),其临床表型包括神经系统表现、转氨酶炎和频繁感染。ALG3 酶催化内质网(ER)管腔聚糖延伸的第一步,将甘露糖从 Dol-P-Man 添加到 Dol-PP-Man5GlcNAc2(Man5)形成 Dol-PP-Man6。这种聚糖延伸是细胞对ER压力做出的第一个也是最快的反应,而ALG3-CDG缺乏这种反应。在这项研究中,我们提供的证据表明,在 ALG3-CDG 患者培养的皮肤成纤维细胞中,未折叠蛋白反应(UPR)和 ER 相关降解活动增加,并且存在由 IRE1-α 通路介导的 UPR 构成性激活。此外,我们还发现,肝源性或非肝源性细胞糖蛋白和分泌的血浆糖蛋白中,N-连接的 Man3-4 聚糖增加。我们发现,与转铁蛋白中的其他 CDG(如 ALG1 或 PMM2-CDG)一样,ALG3-CDG 中的组装中间体 Man5 很可能通过高尔基甘露糖苷酶和糖基转移酶进一步加工成一种独特的聚糖 NeuAc1Gal1GlcNAc1Man3GlcNAc2。我们预测它是一种单链脲聚糖,分子量与 MGAT2-CDG 中描述的截短聚糖相同。总之,本研究阐明了 ALG3-CDG 中糖延伸缺陷所导致的多种以前未认识到的生化后果,这将对 CDG 的发病机制产生重要影响。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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