Reference - Detail
| RRC ID | 45256 |
|---|---|
| Author | Yabu T, Shiba H, Shibasaki Y, Nakanishi T, Imamura S, Touhata K, Yamashita M. |
| Title | Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling. |
| Journal | Cell Death Differ |
| Abstract |
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. |
| Volume | 22(2) |
| Pages | 258-73 |
| Published | 2015-2-1 |
| DOI | 10.1038/cdd.2014.128 |
| PII | cdd2014128 |
| PMID | 25168245 |
| PMC | PMC4291487 |
| MeSH | Animals Apoptosis* Cell Line Ceramides / metabolism* Enzyme Activation Humans JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors JNK Mitogen-Activated Protein Kinases / metabolism* Jurkat Cells MAP Kinase Signaling System* Phosphorylation Sphingomyelin Phosphodiesterase / metabolism* Zebrafish |
| IF | 10.717 |
| Times Cited | 46 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | Jurkat |