PDF(Pubmed)
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.
摘要：
ALG3-CDG是一种罕见的先天性糖基化疾病（CDG），其临床表型包括神经系统表现，转胺炎,和频繁的感染。ALG3酶通过将甘露糖从Dol-P-Man添加到Dol-PP-Man5GlcNAc2（Man5）形成Dol-PP-Man6来催化内质网（ER）腔聚糖延伸的第一步。这种聚糖延伸是对ER应激的第一个也是最快的细胞反应，ALG3-CDG缺乏。在这项研究中,我们提供的证据表明,在ALG3-CDG患者来源的培养皮肤成纤维细胞中,未折叠蛋白反应(UPR)和ER相关降解活性增加,并且存在由IRE1-α途径介导的UPR的组成型激活.此外,我们显示，N-连接的Man3-4聚糖在细胞糖蛋白和分泌的血浆糖蛋白中增加，具有肝或非肝起源。我们发现，像其他CDG，如ALG1-或PMM2-CDG，在转铁蛋白中，ALG3-CDG中的组装中间Man5，可能进一步加工成不同的聚糖，NeuAc1Gal1GlcNAc1Man3GlcNAc2，可能是由高尔基体甘露糖苷酶和糖基转移酶。我们预测它是单触角聚糖，其分子量与MGAT2-CDG中描述的截短聚糖相同。总之,这项研究阐明了ALG3-CDG中聚糖延伸缺陷的多种先前未被认识到的生化后果,这将在CDG的发病机制中具有重要意义.
