Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan.
Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan.
Mol Cell Biochem. 2023 Jun;478(6):1281-1291. doi: 10.1007/s11010-022-04591-1. Epub 2022 Oct 27.
Immunophilins are a family of proteins encompassing FK506-binding proteins (FKBPs) and cyclophilins (Cyps). FKBPs and Cyps exert peptidyl-prolyl cis-trans isomerase (PPIase) activity, which facilitates diverse protein folding assembly, or disassembly. In addition, they bind to immunosuppressant medications where FKBPs bind to tacrolimus (FK506) and rapamycin, whereas cyclophilins bind to cyclosporin. Some large immunophilins have domains other than PPIase referred to as tetratricopeptide (TPR) domain, which is involved in heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp 70) chaperone interaction. The TPR domain confers immunophilins' pleotropic actions to mediate various physiological and biochemical processes. So far, immunophilins have been implicated to play an important role in pathophysiology of inflammation, cancer and neurodegenerative disorders. However, their importance in the development of fibrosis has not yet been elucidated. In this review we focus on the pivotal functional and mechanistic roles of different immunophilins in fibrosis establishment affecting various organs. The vast majority of the studies reported that cyclophilin A, FKBP12 and FKBP10 likely induce organ fibrosis through the calcineurin or TGF-β pathways. FKBP51 demonstrated a role in myelofibrosis development through calcineurin-dependant pathway, STAT5 or NF-κB pathways. Inhibition of these specific immunophilins has been shown to decrease the extent of fibrosis suggesting that immunophilins could be a novel promising therapeutic target to prevent or reverse fibrosis.
免疫亲和素是一类蛋白家族，包括 FK506 结合蛋白（FKBP）和亲环素（Cyps）。FKBP 和 Cyps 具有肽基脯氨酰顺反异构酶（PPIase）活性，有助于多种蛋白质折叠组装或解组装。此外，它们还与免疫抑制剂药物结合，其中 FKBP 结合他克莫司（FK506）和雷帕霉素，而亲环素结合环孢素。一些大型免疫亲和素具有除 PPIase 以外的其他结构域，称为四肽重复（TPR）结构域，该结构域参与热休克蛋白 90（Hsp90）和热休克蛋白 70（Hsp 70）伴侣蛋白的相互作用。TPR 结构域赋予免疫亲和素的多效性作用，以介导各种生理和生化过程。到目前为止，免疫亲和素已被证明在炎症、癌症和神经退行性疾病的病理生理学中发挥重要作用。然而，它们在纤维化发展中的重要性尚未阐明。在这篇综述中，我们重点讨论了不同免疫亲和素在影响各种器官纤维化形成中的关键功能和机制作用。绝大多数研究报告称，亲环素 A、FKBP12 和 FKBP10 可能通过钙调神经磷酸酶或 TGF-β途径诱导器官纤维化。FKBP51 通过钙调神经磷酸酶依赖性途径、STAT5 或 NF-κB 途径在骨髓纤维化的发展中发挥作用。抑制这些特定的免疫亲和素已被证明可以减少纤维化的程度，这表明免疫亲和素可能是预防或逆转纤维化的一种有前途的新型治疗靶点。
