Association between mitochondrial quality control and Parkinson's disease by FKBP38

Shh信号通路在动物中是保守的，在胚胎发育、成体干细胞的维持和癌症中起着关键作用。FKBP38已被证明以细胞自主的方式发挥作用，以防止Shh途径的不适当激活。然而，目前还不清楚FKBP38是如何抑制Shh信号的。通过使用蛋白质组学的方法来发现与FKBP38相关的调节Shh信号的蛋白质，我们现在已经确定ANKMY2是一个与FKBP38相互作用的分子。在小鼠胚胎成纤维细胞中，ANKMY2的缺失或过表达分别导致Shh信号的下调和上调。此外，FKBP38和ANKMY2的联合缺失减弱了这些细胞中的Shh信号，提示ANKMY2作用于FKBP38下游激活Shh信号通路。因此，我们的研究结果表明，FKBP38-ANKMY2轴在体内Shh信号的调节中起着关键作用。

Shh signaling pathway is conserved among animals and has pivotal roles in embryonic development, in the maintenance of adult stem cells, and in cancer. FKBP38 has been shown to act in a cell-autonomous manner to prevent inappropriate activation of the Shh pathway. It has remained unclear, however, how FKBP38 suppresses Shh signaling.With the use of a proteomics approach to the discovery of proteins that regulate Shh signaling in association with FKBP38, we have now identified ANKMY2 as a molecule that interacts with FKBP38. Depletion or overexpression of ANKMY2 resulted in down- and up-regulation of Shh signaling, respectively, in mouse embryonic fibroblasts. Furthermore, combined depletion of both FKBP38 and ANKMY2 attenuated Shh signaling in these cells, suggesting that ANKMY2 acts downstream of FKBP38 to activate the Shh signaling pathway. Our findings thus indicate that the FKBP38-ANKMY2 axis plays a key role in regulation of Shh signaling in vivo.