PDF(Pubmed)
Abstract：
Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.
摘要：
鞘脂在膜结构和细胞信号传导中具有关键功能。神经酰胺是鞘脂代谢的中心分子,并且由神经酰胺合酶(CerS)在从头途径中产生。尽管它们的关键功能，调节CerS的机制仍然未知。使用无偏见的蛋白质组学方法，我们发现小的热休克蛋白27（Hsp27）与CerS1而不是其他CerS特异性相互作用。功能上,我们的数据显示Hsp27是CerS1的内源性抑制剂.野生型Hsp27，但不是CerS1结合缺陷的突变体，抑制CerS1活性。此外,Hsp27的沉默增强了CerS1产生的神经酰胺在细胞中的积累。此外，Hsp27的磷酸化在急性应激反应条件下调节Hsp27-CerS1相互作用和CerS1活性。生物学,我们显示Hsp27敲低会阻碍线粒体功能并以CerS1依赖性方式诱导致死性线粒体自噬。总的来说,我们通过与Hsp27的蛋白质-蛋白质相互作用确定了CerS1调节和CerS1介导的线粒体自噬的重要模式。
