Ceramide synthase 1 is regulated by proteasomal mediated turnover.
Ceramide synthase 1 is regulated by proteasomal mediated turnover.
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神经酰胺合酶 1 受蛋白酶体介导的周转调节。
DOI：
10.1016/j.bbamcr.2009.04.006
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Alexander,Stephen
中科院分区：
文献类型：
--
作者：
Sridevi,Priya;Alexander,Hannah;Laviad,EladL;Pewzner-Jung,Yael;Hannink,Mark;Futerman,AnthonyH;Alexander,Stephen
神经酰胺是一种重要的生物活性脂质，与许多细胞功能密切相关，包括细胞死亡的调节以及癌症和化疗。神经酰胺是由二氢鞘氨醇和酰基 CoA 通过 6 种神经酰胺合酶家族从头合成的，每种酶对不同的脂肪酰基 CoA 底物具有独特的偏好，并且具有独特的组织分布。然而，人们对这些重要酶的调节知之甚少。在这项研究中，我们重点关注神经酰胺合酶 1 (CerS1)，它是结构和功能上最独特的酶，并描述了一种通过泛素化和蛋白酶体依赖性蛋白质周转来特异性控制 CerS1 水平的调节机制。我们发现内源性和异位表达的 CerS1 都具有快速的基础周转，并且包括化疗药物、紫外线和 DTT 在内的多种应激都可以诱导 CerS1 周转。周转需要 CerS1 活性，并受 p38 MAP 激酶和蛋白激酶 C (PKC) 的相反作用调节。 p38 MAP 激酶是周转的正调节因子，而 PKC 是周转的负调节因子。 CerS1 在体内被磷酸化，PKC 的激活会增加蛋白质的磷酸化。这项研究揭示了一种新颖且高度特异性的机制，通过该机制调节 CerS1 蛋白水平并直接影响神经酰胺稳态。
Ceramide is an important bioactive lipid, intimately involved in many cellular functions, including the regulation of cell death, and in cancer and chemotherapy. Ceramide is synthesized de novo from sphinganine and acyl CoA via a family of 6 ceramide synthase enzymes, each having a unique preference for different fatty acyl CoA substrates and a unique tissue distribution. However, little is known regarding the regulation of these important enzymes. In this study we focus on ceramide synthase 1 (CerS1) which is the most structurally and functionally distinct of the enzymes, and describe a regulatory mechanism that specifically controls the level of CerS1 via ubiquitination and proteasome dependent protein turnover. We show that both endogenous and ectopically expressed CerS1 have rapid basal turnover and that diverse stresses including chemotherapeutic drugs, UV light and DTT can induce CerS1 turnover. The turnover requires CerS1 activity and is regulated by the opposing actions of p38 MAP kinase and protein kinase C (PKC). p38 MAP kinase is a positive regulator of turnover, while PKC is a negative regulator of turnover. CerS1 is phosphorylated in vivo and activation of PKC increases the phosphorylation of the protein. This study reveals a novel and highly specific mechanism by which CerS1 protein levels are regulated and which directly impacts ceramide homeostasis.
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影响因子：
4.1
作者：
Mizutani, Y;Kihara, A;Igarashi, Y
通讯作者：
Igarashi, Y
影响因子：
64.5
作者：
GREEN, N;ALEXANDER, H;LERNER, RA
通讯作者：
LERNER, RA
影响因子：
5.3
作者：
Knudsen, KE;Booth, D;Knudsen, ES
通讯作者：
Knudsen, ES
影响因子：
8
作者：
Baldwin, R. M.;Garratt-Lalonde, M.;Lorimer, I. A. J.
通讯作者：
Lorimer, I. A. J.
影响因子：
4.1
作者：
Mizutani, Yukiko;Kihara, Akio;Igarashi, Yasuyuki
通讯作者：
Igarashi, Yasuyuki