Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling.
Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling.
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DOI：
10.1038/cdd.2014.128
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发表时间：
2015-02
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
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中性鞘磷脂酶 (nSMase) 响应环境应激或炎症细胞因子刺激而激活，产生第二信使神经酰胺，介导应激诱导的细胞凋亡。然而，这一过程背后的信号通路和激活机制尚未阐明。在这里，我们表明 c-Jun N 末端激酶 (JNK) 信号传导对 nSMase1（鞘磷脂磷酸二酯酶 2，SMPD2）的磷酸化可刺激神经酰胺生成和细胞凋亡，并为整合脊椎动物细胞中应激和细胞因子激活的细胞凋亡的信号传导机制提供证据。 nSMase1 被鉴定为 JNK 底物，负责其对应激和细胞因子诱导的影响的磷酸化位点是 Ser-270。在斑马鱼细胞中，用 Ser-270 替代丙氨酸会阻断 nSMase1 的磷酸化和激活，而用 Ser-270 替代带负电荷的谷氨酸则模拟了磷酸化的效果。 JNK 抑制剂 SP600125 阻断 nSMase1 的磷酸化和激活，从而阻断神经酰胺信号传导和细胞凋亡。多种应激条件，包括热休克、紫外线照射、过氧化氢处理和抗 Fas 抗体刺激，导致斑马鱼胚胎 ZE 和人 Jurkat T 细胞中 nSMase1 磷酸化、激活 nSMase1，并诱导神经酰胺生成和凋亡。此外，通过 RNAi 敲低来消除 MAPK8/9 或 SMPD2 会减少 Jurkat 细胞中神经酰胺的生成以及应激和细胞因子诱导的细胞凋亡。因此，nSMase1 的磷酸化是 JNK 信号转导中的关键步骤，导致应激条件下和响应细胞因子刺激时神经酰胺的生成和细胞凋亡。 nSMase1 在应激、细胞因子反应和细胞凋亡过程中的神经酰胺信号传导中具有共同的核心作用。
Neutral sphingomyelinase (nSMase) activation in response to environmental stress or inflammatory cytokine stimuli generates the second messenger ceramide, which mediates the stress-induced apoptosis. However, the signaling pathways and activation mechanism underlying this process have yet to be elucidated. Here we show that the phosphorylation of nSMase1 (sphingomyelin phosphodiesterase 2, SMPD2) by c-Jun N-terminal kinase (JNK) signaling stimulates ceramide generation and apoptosis and provide evidence for a signaling mechanism that integrates stress- and cytokine-activated apoptosis in vertebrate cells. An nSMase1 was identified as a JNK substrate, and the phosphorylation site responsible for its effects on stress and cytokine induction was Ser-270. In zebrafish cells, the substitution of Ser-270 for alanine blocked the phosphorylation and activation of nSMase1, whereas the substitution of Ser-270 for negatively charged glutamic acid mimicked the effect of phosphorylation. The JNK inhibitor SP600125 blocked the phosphorylation and activation of nSMase1, which in turn blocked ceramide signaling and apoptosis. A variety of stress conditions, including heat shock, UV exposure, hydrogen peroxide treatment, and anti-Fas antibody stimulation, led to the phosphorylation of nSMase1, activated nSMase1, and induced ceramide generation and apoptosis in zebrafish embryonic ZE and human Jurkat T cells. In addition, the depletion of MAPK8/9 or SMPD2 by RNAi knockdown decreased ceramide generation and stress- and cytokine-induced apoptosis in Jurkat cells. Therefore the phosphorylation of nSMase1 is a pivotal step in JNK signaling, which leads to ceramide generation and apoptosis under stress conditions and in response to cytokine stimulation. nSMase1 has a common central role in ceramide signaling during the stress and cytokine responses and apoptosis.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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通讯作者：
Shayman, JA
影响因子：
11.4
作者：
Jaffrezou, JP;Levade, T;Laurent, G
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影响因子：
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