Molecular chaperones, many of which are heat shock proteins (Hsps), are components of the chaperoning system and when defective can cause disease, the chaperonopathies. Chaperone-gene variants cause genetic chaperonopathies, whereas in the acquired chaperonopathies the genes are normal, but their protein products are not, due to aberrant post-transcriptional mechanisms, e.g. post-translational modifications (PTMs). Since the chaperoning system is widespread in the body, chaperonopathies affect various tissues and organs, making these diseases of interest to a wide range of medical specialties. Genetic chaperonopathies are uncommon but the acquired ones are frequent, encompassing various types of cancer, and inflammatory and autoimmune disorders. The clinical picture of chaperonopathies is known. Much less is known on the impact that pathogenic mutations and PTMs have on the properties and functions of chaperone molecules. Elucidation of these molecular alterations is necessary for understanding the mechanisms underpinning the tissue and organ abnormalities occurring in patients. To illustrate this issue, we discuss structural-functional alterations caused by mutation in the chaperones CCT5 and HSPA9, and PTM effects on Hsp60. The data provide insights into what may happen when CCT5 and HSPA9 malfunction in patients, e.g. accumulation of cytotoxic protein aggregates with tissue destruction; or for Hsp60 with aberrant PTM, degradation and/or secretion of the chaperonin with mitochondrial damage. These and other possibilities are now open for investigation. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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伴侣病的分子机制：了解组织病理学异常和开发新疗法的线索。

分子伴侣，其中许多是热激蛋白（Hsps），是伴侣系统的组成部分，当缺陷分子可以引起疾病时，就是伴侣病。伴侣基因变体引起遗传性伴侣病，而在获得性伴侣病中，基因是正常的，但由于异常的转录后机制，例如翻译后修饰（PTM），其蛋白产物不是。由于伴侣系统在人体中广泛分布，伴侣病会影响各种组织和器官，使这些疾病成为医学广泛领域的关注对象。遗传性伴侣病并不常见，但后天却很常见，包括各种类型的癌症以及炎症性和自身免疫性疾病。伴侣病的临床图片是已知的。关于致病突变和PTM对伴侣分子的特性和功能的影响知之甚少。阐明这些分子改变对于理解支撑患者中发生的组织和器官异常的机制是必要的。为了说明这个问题，我们讨论了由伴侣CCT5和HSPA9突变引起的结构功能改变，以及PTM对Hsp60的作用。数据提供了对患者CCT5和HSPA9发生故障时可能发生的情况的见解，例如细胞毒性蛋白聚集体的积累与组织破坏的积累；或对于PTM异常的Hsp60，伴随着线粒体损伤的伴侣蛋白的降解和/或分泌。这些和其他可能性现在可供研究。©2019英国和爱尔兰病理学会。