Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Columbus Center, Baltimore, MD, USA.
Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.
J Pathol. 2020 Jan;250(1):9-18. doi: 10.1002/path.5349. Epub 2019 Nov 22.
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.
分子伴侣，其中许多是热休克蛋白（Hsps），是伴侣系统的组成部分，当它们发生缺陷时会导致疾病，即伴侣病。伴侣基因变异会导致遗传性伴侣病，而在获得性伴侣病中，基因是正常的，但它们的蛋白质产物由于异常的转录后机制（如翻译后修饰（PTMs））而不正常。由于伴侣系统在体内广泛存在，伴侣病会影响各种组织和器官，因此这些疾病引起了广泛的医学专业关注。遗传性伴侣病并不常见，但获得性伴侣病很常见，包括各种类型的癌症以及炎症和自身免疫性疾病。伴侣病的临床特征是已知的。对于致病突变和 PTMs 对伴侣分子的性质和功能的影响，人们了解得要少得多。阐明这些分子变化对于理解发生在患者身上的组织和器官异常的机制是必要的。为了说明这个问题，我们讨论了伴侣蛋白 CCT5 和 HSPA9 突变以及 PTM 对 Hsp60 产生的结构-功能改变。这些数据提供了一些见解，说明当 CCT5 和 HSPA9 在患者中出现故障时可能会发生什么，例如细胞毒性蛋白聚集体的积累导致组织破坏；或者对于具有异常 PTM 的 Hsp60，伴侣蛋白的降解和/或分泌以及线粒体损伤。现在可以对这些和其他可能性进行研究。©2019 英国和爱尔兰病理学会。由 John Wiley & Sons, Ltd 出版。
