ZFIN ID: ZDB-PUB-140830-12
Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling
Yabu, T., Shiba, H., Shibasaki, Y., Nakanishi, T., Imamura, S., Touhata, K., Yamashita, M.
Date: 2015
Source: Cell death and differentiation   22(2): 258-73 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • 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
PubMed: 25168245 Full text @ Cell Death Differ.
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.Cell Death and Differentiation advance online publication, 29 August 2014; doi:10.1038/cdd.2014.128.