TNFR1-mediated ceramide production

TNF-alpha activates sphingomyelinase (SMASE) proteins to catalyze hydrolysis of sphingomyeline into ceramide. Two types of SMASE can be distinguished downstream of TNFR1 signaling, acid and neutral SMASEs (Adam-Klages S et al. 1996, 1998). Neutral SMASE (such as SMPD2,3) has a pH optimum of 7.4, requires Mg2+ ions and is found at the plasma membrane (Rao BG and Spence MW 1976). Acid SMASE is active at pH 4-5, is Zn2+-dependent and is mainly localized in the lysosomes. The death domain of TNFR1 that is responsible for the initiation of the apoptotic pathway also mediates activation of an acid SMASE. The two proapoptotic adaptor proteins TRADD and FADD are also involved in the activation of acid SMASE signaling events (Schwandner R et al. 1998). TNF-alpha can also activate the pro-apoptotic acidic SMASE via caspase-8 mediated activation of caspase-7 which in turn proteolytically cleaves and activates the 72kDa pro-acid SMASE form (Edelmann B et al. 2011). Neutral SMASE(SMPD) binds to adaptor protein NSMAF (FAN), which bridges it to NSMASE-activating domain (NSD) of TNFR1 (Adam D et al. 1996; Adam-Klages S et al. 1996; Ségui B et al. 2001). Activation of SMPD2,3 leads to an accumulation of ceramide at the cell surface.<p>Ceramide metabolism generates a cascade of bioactive lipids, all of which carry a specific signaling capacity. Ceramide can be converted by ceramidase into sphingosine, which in turn is phosphorylated by sphingosine kinase into sphingosine-1-phosphate (S1P). These lipids exert opposite biological effects: ceramide and sphingosine are able to induce anti-proliferative and pro-apoptotic responses, whereas S1P is a cytoprotective molecule that promotes cell growth and counteracts apoptotic stimuli (Cuvillier O et al.1996)

TNF-α（肿瘤坏死因子-α）激活鞘磷脂酶（SMASE）蛋白，催化鞘磷脂的水解生成鞘氨醇。在TNFR1信号通路下游，可区分出两种类型的SMASE：酸性SMASE和中性SMASE（Adam-Klages S 等人，1996，1998）。中性SMASE（如SMPD2、3）的pH最适值为7.4，需要Mg2+离子，并位于质膜上（Rao BG 和 Spence MW，1976）。酸性SMASE在pH 4-5时活性最高，依赖于Zn2+，主要定位于溶酶体。负责启动凋亡通路的TNFR1的死亡结构域也介导酸性SMASE的激活。两种促凋亡适配蛋白TRADD和FADD也参与酸性SMASE信号事件的激活（Schwandner R 等人，1998）。TNF-α还可以通过caspase-8介导的caspase-7激活，进而通过蛋白水解切割和激活72kDa的促凋亡酸性SMASE前体（Edelmann B 等人，2011）。中性SMASE（SMPD）与适配蛋白NSMAF（FAN）结合，该适配蛋白将SMPD连接到TNFR1的NSMASE激活域（NSD）（Adam D 等人，1996；Adam-Klages S 等人，1996；Ségui B 等人，2001）。SMPD2、3的激活导致鞘氨醇在细胞表面的积累。鞘氨醇代谢产生一系列生物活性脂质，所有这些脂质都携带特定的信号传导能力。鞘氨醇可被鞘氨醇酶转化为鞘氨醇，鞘氨醇随后被鞘氨醇激酶磷酸化为鞘氨醇-1-磷酸（S1P）。这些脂质具有相反的生物学效应：鞘氨醇和鞘氨醇可诱导抗增殖和促凋亡反应，而S1P是一种细胞保护分子，可促进细胞生长并对抗凋亡刺激（Cuvillier O 等人，1996）。