Regulation of the amount of ceramide-1-phosphate synthesized in differentiated human podocytes
Regulation of the amount of ceramide-1-phosphate synthesized in differentiated human podocytes
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DOI：
10.1016/j.bbalip.2019.158517
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发表时间：
2019-12-01
影响因子：
4.8
通讯作者：
Fornoni, Alessia
中科院分区：
文献类型：
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作者：
Mallela, Shamroop Kumar;Mitrofanova, Alla;Fornoni, Alessia
鞘脂作为细胞的结构组分具有重要的功能，但它们也作为调节不同细胞过程的信号传导分子，例如凋亡、细胞增殖、细胞迁移、细胞分裂和炎症。因此，鞘脂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ORM 1/2蛋白的直向同源物，其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（SMPDL 3b）是质膜（PM）中的糖基磷脂酰肌醇（GPI）锚定蛋白，并决定巨噬细胞中的膜流动性。我们先前表明，SMPDL 3b的差异表达改变了人足细胞中神经酰胺-1-磷酸（C1 P）的可用性，足细胞是肾脏滤过屏障的终末分化细胞。这一观察结果使我们研究SMPDL 3b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C1 P的可用性。我们发现SMPDL 3b与CERK相互作用，并在体外与C1 P结合。此外，当SMPDL 3b表达沉默时，CERK表达减少。这些观察结果使我们提出，SMPDL 3b影响足细胞中可用的C1 P量的机制之一是通过干扰CERK的功能，从而维持足细胞中C1 P水平的平衡。
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.