Ceramide triggers an NF-κB-dependent survival pathway through calpain
Ceramide triggers an NF-κB-dependent survival pathway through calpain
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DOI：
10.1038/sj.cdd.4401592
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发表时间：
2005-05-01
影响因子：
12.4
通讯作者：
Schneider, C
中科院分区：
文献类型：
--
作者：
Demarchi, F;Bertoli, C;Schneider, C
我们已经表明，C2神经酰胺，这种脂质第二信使的细胞渗透性类似物，触发NF-κ B依赖的生存途径，抵消细胞死亡。NF-κ B的激活和随后的促存活基因的诱导依赖于钙蛋白酶活性，并且通过沉默钙蛋白酶小亚基（Capn 4）来阻止，所述钙蛋白酶小亚基（Capn 4）是普遍存在的钙蛋白酶的功能所需的。我们已经证明，p105（NF-κ B1）和它的蛋白水解产物p50可以在体外的微和毫钙蛋白酶的目标和p50缺失突变体，缺乏的N-和C-末端，是耐钙蛋白酶介导的降解。Capn 4沉默导致多种人类细胞系中内源性p105和p50的稳定。此外，在钙蛋白酶活性缺陷的Capn 4-/-小鼠胚胎成纤维细胞中，NF-κ B存活基因响应C2神经酰胺的p105加工和活化受损。总之，这些数据表明存在具有促生存功能的神经酰胺-钙蛋白酶-NF-κ B轴。
We have shown that C2 ceramide, a cell-permeable analog of this lipid second messenger, triggers an NF-kappa B dependent survival pathway that counteracts cell death. Activation of NF-kappa B and subsequent induction of prosurvival genes relies on calpain activity and is prevented on silencing of the calpain small subunit (Capn4) that is required for the function of ubiquitous calpains. We have demonstrated that p105 (NF-kappa B1) and its proteolytic product p50 can be targets of microand milli-calpain in vitro and that a p50 deletion mutant, lacking both the N- and the C-terminal ends, is resistant to calpain-mediated degradation. Capn4 silencing results in stabilization of endogenous p105 and p50 in diverse human cell lines. Furthermore, p105 processing and activation of NF-kappa B survival genes in response to C2 ceramide is impaired in Capn4-/- mouse embryonic fibroblasts defective in calpain activity. Altogether, these data argue for the existence of a ceramide - calpain - NF-kappa B axis with prosurvival functions.