Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Cell Death Dis. 2013 Nov 21;4(11):e929. doi: 10.1038/cddis.2013.451.
The involvement of ceramide in death receptor-mediated apoptosis has been widely examined with most studies focusing on the role of ceramide generated from sphingomyelin hydrolysis. We now analyze the effect of the ceramide acyl chain length by studying tumor necrosis factor α receptor-1 (TNFR1)-mediated apoptosis in a ceramide synthase 2 (CerS2) null mouse, which cannot synthesize very-long acyl chain ceramides. CerS2 null mice were resistant to lipopolysaccharide/galactosamine-mediated fulminant hepatic failure even though TNFα secretion from macrophages was unaffected. Cultured hepatocytes were also insensitive to TNFα-mediated apoptosis. In addition, in both liver and in hepatocytes, caspase activities were not elevated, consistent with inhibition of TNFR1 pro-apoptotic signaling. In contrast, Fas receptor activation resulted in the death of CerS2 null mice. Caspase activation was blocked because of the inability of CerS2 null mice to internalize the TNFR1; whereas Fc-TNFα was internalized to a perinuclear region in hepatocytes from wild-type mice, no internalization was detected in CerS2 null mice. Our results indicate that altering the acyl chain composition of sphingolipids inhibits TNFR1 internalization and inhibits selective pro-apoptotic downstream signaling for apoptosis.
神经酰胺在死亡受体介导的细胞凋亡中的作用已经得到了广泛的研究，大多数研究都集中在鞘磷脂水解产生的神经酰胺的作用上。我们现在通过研究神经酰胺合酶 2（CerS2）缺失小鼠（不能合成非常长链酰基神经酰胺）来分析神经酰胺酰链长度的影响。CerS2 缺失的小鼠对脂多糖/半乳糖胺介导的暴发性肝衰竭有抗性，尽管巨噬细胞中 TNFα 的分泌不受影响。培养的肝细胞对 TNFα 介导的细胞凋亡也不敏感。此外，在肝脏和肝细胞中， caspase 活性没有升高，这与 TNFR1 促凋亡信号的抑制一致。相反，Fas 受体的激活导致 CerS2 缺失的小鼠死亡。 caspase 的激活被阻断，因为 CerS2 缺失的小鼠不能内化 TNFR1；而 Fc-TNFα在野生型小鼠的肝细胞中被内化到核周区域，在 CerS2 缺失的小鼠中则没有检测到内化。我们的结果表明，改变神经鞘脂的酰链组成会抑制 TNFR1 的内化，并抑制凋亡的选择性促凋亡下游信号。
