Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones.
Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones.
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DOI：
10.1210/edrv.19.2.0327
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发表时间：
1998-04
影响因子：
20.3
通讯作者：
P. Kim;P. Arvan
中科院分区：
文献类型：
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作者：
P. Kim;P. Arvan
从本综述中描述的研究，很明显，结构信息不仅决定了可输出蛋白的功能特性，而且还决定了它们在细胞内分泌途径中被转运的能力。在ERSD中，缺陷的确切性质决定了表型的严重程度和遗传方式。据我们所知，所有遗传性ERSD都可归因于可输出蛋白编码序列的突变;迄今为止，除无β脂蛋白血症（见第IV.D节）外，没有ER伴侣蛋白突变（科学家通过基因工程改造的突变除外）被报告为自发性疾病的原因。ERSD中ER分子伴侣的升高在突变之间、组织之间、个体患者之间和不同生理状态之间（即，例如在激素替代疗法之前和之后）。因此，ER伴侣蛋白水平的测量起着重要的诊断作用，但可能不应该被用作对这些疾病进行分类的唯一依据。此外，由于已报道突变分泌蛋白几乎发生在每个器官系统中，ERSD更容易在细胞生物学水平上分类，通过实际合成分泌蛋白的细胞的反应，而不是在终末器官水平上与疾病相关的激素缺乏。考虑到这些想法，我们在图4中给出了一个示意图。根据这一模式，所有ERSD开始与受影响的蛋白质或其亚基的ER保留。然后突变体可以分为两组：A型，其中尽管蛋白质是转运缺陷的，但生物活性被保留;和B型，其中突变体没有功能活性的潜力。这两种类型都包括隐性和显性突变。这两类之间的主要临床差异是A型ERSD可能适用于设计用于下调ER输出的质量控制的疗法，使得潜在的功能性分子可以逃离ER并到达其预期的细胞内目的地。在这两种类型的ERSD中，在大多数情况下，保留的突变蛋白在ER中有效降解（亚型A-I和B-I）。在这些情况下，主要的全球表型涉及激素缺乏的症状和体征。然而，仔细的生物化学和细胞生物学研究揭示了腺体功能的各种异常，通常包括一种或多种ER分子伴侣水平的升高。如第I. C节所述，这种升高是长期适应未折叠突变分泌蛋白（其合成受到内分泌反馈环的刺激）的结果。如第III节所述，升高的分子伴侣似乎与ER保留以及可能去除错误折叠蛋白的ERAD过程整体相关。在这些情况下，ER区室可能会扩张，但分泌细胞可能会存活。在更不寻常的亚型II（亚型B-II，可能还有A-II）中，突变蛋白表现出抵抗ERAD的内在倾向，造成潜在危险的不可消化物质积累（图4）。这可能是由于不寻常的生产新的，蛋白酶抗性的蛋白质复合物，或者它可能是由于蛋白质组装体的形成，防止反向易位的突变蛋白质的胞质溶胶的蛋白酶体蛋白水解。未转运的突变蛋白对ER相关降解的抗性将导致显性ERSD（460）。在这种情况下，虽然突变等位基因可以与野生型等位基因形成寡聚杂交体，但正常输出的野生型等位基因的完全非混合和突变等位基因的毒性积累是另一种不同的情况，也可以产生显性遗传模式。（摘要截断）
From the studies described in this review, it is clear that structural information dictates not only the functional properties of exportable proteins, but also their ability to be transported in the intracellular secretory pathway. In ERSDs, the precise nature of the defect determines both the severity of the phenotype and the mode of inheritance. To our knowledge, all genetically inherited ERSDs are attributable to mutations in the coding sequence of exportable proteins; thus far, with the exception of abetalipoproteinemia (see Section IV.D), no mutations in ER chaperones (other than those that scientists have genetically engineered) have been reported as the cause of spontaneous disease. The elevations of ER chaperones in ERSDs may differ between mutations, between tissues, between individual patients, and between different physiological states (i.e., such as before and after hormone replacement therapy) in the same patient. Thus, measurement of ER chaperone levels plays an important diagnostic role, but probably should not be used as the sole basis to classify these illnesses. Moreover, because mutant secretory proteins have been reported to occur in virtually every organ system, ERSDs are more readily classified at the cell biological level, by the responses of the cells that actually synthesize the secretory protein, rather than the hormone deficiency associated with the illness at the end-organ level. With these ideas in mind, we present a schematic view in Fig. 4. According to this schema, all ERSDs begin with ER retention of the affected proteins or their subunits. Mutants may then be divided into two groups: type A, where the biological activity is preserved although the protein is transport-deficient; and type B, where the mutant has no potential for functional activity. Both categories include both recessive and dominant mutations. The primary clinical difference between these two classes is that type A ERSDs may be amenable to therapies designed to down-regulate the quality control of ER export so that potentially functional molecules can escape the ER and reach their intended intracellular destination. In both types of ERSDs, in most cases, the retained mutant protein is efficiently degraded in the ER (subtypes A-I and B-I). In these cases, the predominant, global phenotypes involve the symptoms and signs of hormone deficiency. However, careful biochemical and cell biological studies reveal various abnormalities in glandular function, typically including the elevation of the levels of one or more ER chaperones. As described in Section I.C, such elevations are a consequence of chronic adaptation to the presence of unfolded mutant secretory protein (the synthesis of which is stimulated all the more by endocrine feedback loops). As described in Section III, the elevated chaperones appear to be integrally related to the ER retention as well as perhaps the ERAD process that removes the misfolded proteins. In these cases, the ER compartment may expand, but the secretory cells are likely to survive. In the more unusual subtype II (subtypes B-II and perhaps A-II), the mutant protein exhibits an intrinsic tendency to resist ERAD, creating a potentially dangerous accumulation of indigestible material (Fig. 4). This may be due to the unusual production of novel, protease-resistant protein complexes, or it may be due to the formation of protein assemblies that prevent the reverse translocation of mutant proteins to the cytosol for proteasomal proteolysis. Resistance of untransported mutant protein to ER-associated degradation will predispose to a dominant ERSD (460). In such a case, although the mutant allele could could form oligomeric hybrids with the wild-type allele, complete nonmixing of the normally exported wild-type allele and toxic accumulation of the mutant allele is another distinct scenario that can also produce a dominant mode of inheritance. (ABSTRACT TRUNCATED)