Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Dec;1864(12):158517. doi: 10.1016/j.bbalip.2019.158517. Epub 2019 Sep 2.
Sphingolipids have important functions as structural components of cells but they also function as signaling molecules regulating different cellular processes such as apoptosis, cell proliferation, cell migration, cell division and inflammation. Hence, a tight regulation of the sphingolipid homeostasis is essential to maintain proper cellular functions. Mammalian ORMDL proteins are orthologues of the yeast ORM1/2 proteins, which regulate ceramide synthesis in yeast. ORMDL proteins inhibit serine palmitoyltransferase (SPT), the enzyme regulating a rate-limiting step of the sphingolipid pathway to control the levels of ceramides and other sphingolipids. Sphingomyelinase phosphodiesterase like 3b (SMPDL3b) is a glycosylphosphatidylinositol (GPI) anchored protein in the plasma membrane (PM) and determines membrane fluidity in macrophages. We previously showed that differential expression of SMPDL3b alters the availability of Ceramide-1-phosphate (C1P) in human podocytes, which are terminally differentiated cells of the kidney filtration barrier. This observation lead us to investigate if SMPDL3b controls C1P availability in human podocytes by interfering with ceramide kinase (CERK) expression and function. We found that SMPDL3b interacts with CERK and can bind to C1P in vitro. Furthermore, CERK expression is reduced when SMPDL3b expression is silenced. These observations led us to propose that one of the mechanisms by which SMPDL3b influences the amount of C1P available in the podocytes is by interfering with the function of CERK thereby maintaining a balance in the levels of the C1P in podocytes.
鞘脂类具有作为细胞结构成分的重要功能，但它们也作为信号分子发挥作用，调节细胞凋亡、细胞增殖、细胞迁移、细胞分裂和炎症等不同的细胞过程。因此，鞘脂类稳态的严格调节对于维持适当的细胞功能至关重要。哺乳动物 ORMDL 蛋白是酵母 ORM1/2 蛋白的同源物，它们调节酵母中的神经酰胺合成。ORMDL 蛋白抑制丝氨酸棕榈酰转移酶（SPT），该酶调节鞘脂途径的限速步骤，以控制神经酰胺和其他鞘脂的水平。鞘磷脂酶磷酸二酯酶样 3b（SMPDL3b）是质膜（PM）中糖基磷脂酰肌醇（GPI）锚定蛋白，决定巨噬细胞中的膜流动性。我们之前表明，SMPDL3b 的差异表达改变了人足细胞中神经酰胺-1-磷酸（C1P）的可用性，足细胞是人肾脏过滤屏障的终末分化细胞。这一观察结果促使我们研究 SMPDL3b 是否通过干扰神经酰胺激酶（CERK）的表达和功能来控制人足细胞中 C1P 的可用性。我们发现 SMPDL3b 与 CERK 相互作用，并可以在体外与 C1P 结合。此外，当 SMPDL3b 表达被沉默时，CERK 表达减少。这些观察结果使我们提出，SMPDL3b 影响足细胞中 C1P 可用性的机制之一是通过干扰 CERK 的功能，从而维持足细胞中 C1P 水平的平衡。
