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首页> 外文期刊>Biochemistry >Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway
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Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway

机译：动态糖基化治理脊椎动物COPII贩运途径

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摘要

The COPII coat complex, which mediates secretory cargo trafficking from the endoplasmic reticulum, is a key control point for subcellular protein targeting. Because misdirected proteins cannot function, protein sorting by COPII is critical for establishing and maintaining normal cell and tissue homeostasis. Indeed, mutations in COPII genes cause a range of human pathologies, including cranio-lenticulo-sutural dysplasia (CLSD), which is characterized by collagen trafficking defects, craniofacial abnormalities, and skeletal dysmorphology. Detailed knowledge of the COPII pathway is required to understand its role in normal cell physiology and to devise new treatments for disorders in which it is disrupted. However, little is known about how vertebrates dynamically regulate COPII activity in response to developmental, metabolic, or pathological cues. Several COPII proteins are modified by O-linked β- N -acetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, but the biochemical and functional effects of these modifications remain unclear. Here, we use a combination of chemical, biochemical, cellular, and genetic approaches to demonstrate that site-specific O-GlcNAcylation of COPII proteins mediates their protein–protein interactions and modulates cargo secretion. In particular, we show that individual O-GlcNAcylation sites of SEC23A, an essential COPII component, are required for its function in human cells and vertebrate development, because mutation of these sites impairs SEC23A-dependent in vivo collagen trafficking and skeletogenesis in a zebrafish model of CLSD. Our results indicate that O-GlcNAc is a conserved and critical regulatory modification in the vertebrate COPII-dependent trafficking pathway.
机译：将分泌物贩运从内质网的分泌物贩运的Copii涂层复合物是亚细胞蛋白靶向的关键控制点。因为误导性蛋白不能起作用，所以Copii的蛋白质分类对于建立和维持正常细胞和组织稳态至关重要。实际上，Copii基因的突变导致一系列人类病理，包括Cranio-LeNticulo-Sutitural Dysplasia（CLSD），其特征在于胶原贩贩运缺陷，颅面异常和骨骼疑难解失用。需要详细了解CoPII途径，以了解其在正常细胞生理中的作用，并设计用于紊乱的新治疗方法。然而，关于脊椎动物如何响应于发育，代谢或病理提示而众所周知。通过O型β-N-乙酰甘氨酸（O-GLCNAC），一种动态形式的细胞内蛋白质糖基化改性了几种COPII蛋白，但这些修饰的生化和功能效果仍不清楚。在这里，我们使用化学，生化，细胞和遗传方法的组合，以证明Copii蛋白的特异性o-glcnacylation介导其蛋白质相互作用并调节货物分泌。特别地，我们表明SEC23a的单个O-GlcnaCylation位点是其在人体细胞和脊椎动物发育中的作用所必需的，因为这些位点的突变损害了Zebrafish模型中的Sec23a依赖于体内胶原蛋白贩运和骨骼发生CLSD。我们的结果表明，O-GLCNAC是脊椎动物依赖贩运途径中的保守和严重的监管改性。

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  • 来源
    《Biochemistry》 |2018年第1期|共17页
  • 作者

    Nathan J. Cox; Gokhan Unlu; Brittany J. Bisnett; Thomas R. Meister; Brett M. Condon; Peter M. Luo; Timothy J. Smith; Michael Hanna; Abhishek Chhetri; Erik J. Soderblom; Anjon Audhya; Ela W. Knapik; Michael Boyce;

  • 作者单位

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

    Departments of Medicine and Cell and Developmental Biology Vanderbilt University Medical Center Nashville Tennessee 37232 United States;

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

    Department of Biomolecular Chemistry University of Wisconsin—Madison School of Medicine and Public Health Madison Wisconsin 53706 United States;

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

    Duke Proteomics and Metabolomics Core Facility Center for Genomic and Computational Biology Duke University Durham North Carolina 27710 United States;

    Department of Biomolecular Chemistry University of Wisconsin—Madison School of Medicine and Public Health Madison Wisconsin 53706 United States;

    Departments of Medicine and Cell and Developmental Biology Vanderbilt University Medical Center Nashville Tennessee 37232 United States;

    Department of Biochemistry and Pharmacological Sciences Training Program Duke University School of Medicine Durham North Carolina 27710 United States;

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  • 正文语种 eng
  • 中图分类 生物化学;
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