FK506 binding (FKBP) proteins are part of the highly conserved immunophilin family and its members have fundamental roles in the regulation of signalling pathways involved in inflammation, adaptive immune responses, cancer and developmental biology. The original member of this family, FKBP12, is a well-known binding partner for the immunosuppressive drugs tacrolimus (FK506) and sirolimus (rapamycin). FKBP12 and its analog, FKBP12.6, function as cis/trans peptidyl prolyl isomerases (PPIase) and they catalyse the interconversion of cis/trans prolyl conformations. Members of this family uniquely contain a PPIase domain, which may not be functional. The larger FKBPs, such as FKBP51, FKBP52 and FKBPL, contain extra regions, including tetratricopeptide repeat (TPR) domains, which are important for their versatile protein-protein interactions with inflammation-related signalling pathways. In this review we focus on the pivotal role of FKBP proteins in regulating glucocorticoid signalling, canonical and non-canonical NF-κB signalling, mTOR/AKT signalling and TGF-β signalling. We examine the mechanism of action of FKBP based immunosuppressive drugs on these cell signalling pathways and how off target interactions lead to the development of side effects often seen in the clinic. Finally, we discuss the latest advances in the role of FKBPs as therapeutic targets and the development of novel agents for a range of indications of unmet clinical need, including glucocorticoid resistance, obesity, stress-induced inflammation and novel cancer immunotherapy.

FK506 结合 (FKBP) 蛋白是高度保守的亲免蛋白家族的一部分，其成员在调节涉及炎症、适应性免疫反应、癌症和发育生物学的信号通路中具有重要作用。该家族的原始成员 FKBP12 是众所周知的免疫抑制药物他克莫司 (FK506) 和西罗莫司 (雷帕霉素) 的结合伙伴。FKBP12 及其类似物 FKBP12.6 充当顺式/反式肽基脯氨酰异构酶 (PPIase)，它们催化顺式/反式的相互转换脯氨酰构象。该家族的成员独特地包含一个 PPIase 域，该域可能不起作用。较大的 FKBP，如 FKBP51、FKBP52 和 FKBPL，包含额外的区域，包括四三肽重复 (TPR) 域，这对于它们与炎症相关信号通路的多功能蛋白质-蛋白质相互作用很重要。在这篇综述中，我们关注 FKBP 蛋白在调节糖皮质激素信号、经典和非经典 NF-κB 信号、mTOR/AKT 信号和 TGF-β 信号中的关键作用。我们研究了基于 FKBP 的免疫抑制药物对这些细胞信号通路的作用机制，以及脱靶相互作用如何导致临床中常见的副作用的发展。最后，