Caspase-dependent and -independent activation of acid sphingomyelinase signaling
Caspase-dependent and -independent activation of acid sphingomyelinase signaling
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DOI：
10.1074/jbc.m414569200
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发表时间：
2005-07-15
影响因子：
4.8
通讯作者：
Kolesnick, R
中科院分区：
文献类型：
--
作者：
Rotolo, JA;Zhang, JJ;Kolesnick, R
最近的证据表明，将质膜筏聚集成神经酰胺丰富的平台是一种跨膜信号机制，用于细胞表面受体的子集和环境应激(Grassme，H.，Jekle，A.，Riehle，A.，Schwarz，H.，Berger，J.，Sandhoff，K.，Kolesnick，R.，和Gulbins，E.(2001)J.Biol)。化学。20589-20596；Cremesti，A.，Paris，F.，Grassme，H.，Holler，N.，Tschopp，J.，Fuks，Z.，Gulbins，E.和Kolesnick，R.(2001年)J.Biol。化学。276、23954-23961)。分泌形式的酸性鞘磷脂酶(ASMase)转移到微小的筏子中，在其中产生驱动筏子结合的神经酰胺。这一过程用于前馈Fas的激活，与caspase 8完全激活的2%类似，足以使ASMase最大限度地易位，导致富神经酰胺平台内形成死亡诱导信号复合体，并导致细胞凋亡。在这里，我们报告用UV-C处理Jurkat T细胞也可以在1分钟内诱导ASMase移位到RAFT中，催化鞘磷脂水解为神经酰胺和RAFT聚集。与Fas不同，紫外线诱导的ASMase转位和激活不依赖于caspase。然而，富含神经酰胺的平台促进了UV-C诱导的死亡信号，因为ASMase抑制或RAFT中断抑制了细胞凋亡，提高了克隆性细胞的存活率。因此，这些研究定义了两种不同的机制，一种是依赖于caspase 8和FADD的Fas介导的机制，另一种是依赖于caspase激活的紫外线诱导机制。与这一观点一致的是，caspase 8或FADD的基因缺失或药物抑制使Jurkat细胞在Fas连接时无法进行鞘脂信号转导和凋亡，但不会损害UV-C刺激下的这些事件。
Recent evidence suggests clustering of plasma membrane rafts into ceramide-enriched platforms serves as a transmembrane signaling mechanism for a subset of cell surface receptors and environmental stresses ( Grassme, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhoff, K., Kolesnick, R., and Gulbins, E. ( 2001) J. Biol. Chem. 276, 20589-20596; Cremesti, A., Paris, F., Grassme, H., Holler, N., Tschopp, J., Fuks, Z., Gulbins, E., and Kolesnick, R. ( 2001) J. Biol. Chem. 276, 23954-23961). Translocation of the secretory form of acid sphingomyelinase ( ASMase) into microscopic rafts generates therein the ceramide that drives raft coalescence. This process serves to feed forward Fas activation, with similar to 2% of full caspase 8 activation sufficient for maximal ASMase translocation, leading to death-inducing signaling complex formation within ceramide-rich platforms, and apoptosis. Here we report that treatment of Jurkat T cells with UV-C also induces ASMase translocation into rafts within 1 min, catalyzing sphingomyelin hydrolysis to ceramide and raft clustering. In contrast to Fas, UV-induced ASMase translocation and activation were caspase-independent. Nonetheless, ceramide-rich platforms promoted UV-C-induced death signaling, because ASMase inhibition or raft disruption inhibited apoptosis, improving clonogenic cell survival. These studies thus define two distinct mechanisms for biologically relevant ASMase activation within rafts; a Fas-mediated mechanism dependent upon caspase 8 and FADD, and a UV-induced mechanism independent of caspase activation. Consistent with this notion, genetic depletion or pharmacologic inhibition of caspase 8 or FADD, which render Jurkat cells incapable of sphingolipid signaling and apoptosis upon Fas ligation, did not impair these events upon UV-C stimulation.