Role of ceramide synthase 2 in G-CSF signaling and G-CSF-R translocation into detergent-resistant membranes
Role of ceramide synthase 2 in G-CSF signaling and G-CSF-R translocation into detergent-resistant membranes
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DOI：
10.1038/s41598-018-37342-8
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发表时间：
2019-01
影响因子：
4.6
通讯作者：
Jennifer Kurz;J. Barthelmes;L. Blum;T. Ulshöfer;Marthe-Susanna Wegner;N. Ferreirós;Luise A Roser;G. Geisslinger;S. Grösch;S. Schiffmann
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文献类型：
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作者：
Jennifer Kurz;J. Barthelmes;L. Blum;T. Ulshöfer;Marthe-Susanna Wegner;N. Ferreirós;Luise A Roser;G. Geisslinger;S. Grösch;S. Schiffmann
神经酰胺是具有特定酰链长度的鞘磷脂，由相应的神经酰胺合成酶(CerS1-6)产生。在多发性硬化症(MS)的动物模型实验性自身免疫性脑脊髓炎(EAE)中，CerS2的消融通过减少中性粒细胞向中枢神经系统的迁移来抑制EAE的病理。这种迁移是由粒细胞集落刺激因子(G-CSF)信号诱导的。G-CSF信号导致信号级联，包括Lyn激酶和STAT3的磷酸化。这反过来调节中性粒细胞表面受体趋化因子受体2(CXCR2)的表达，并导致该受体移位到抗洗涤剂膜(DRM)。在本研究中，我们研究了神经酰胺在G-CSF信号转导中的作用。我们发现，G-CSF处理野生型骨髓细胞(BMC)会导致G-CSF受体(G-CSF-R)移位到DRM中。G-CSF还可诱导WT和CerS2缺失的骨髓细胞中神经酰胺的下调，以及超长链乳糖基神经酰胺的上调。然而，在CerS2缺失的骨髓细胞中，G-CSF不能诱导G-CSF-R转位到DRM中，导致Lyn的磷酸化减少，CXCR2的表达减少。有趣的是，CerS6缺失的骨髓细胞中的G-CSF信号没有受到影响。综上所述，超长链神经酰胺在G-CSF信号转导和G-CSF-R向DRM的转位中起重要作用。
Ceramides are sphingolipids with defined acyl chain lengths, which are produced by corresponding ceramide synthases (CerS1-6). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), the ablation of CerS2 suppresses EAE-pathology by reducing neutrophil migration into the central nervous system. This migration is induced by granulocyte-colony stimulating factor (G-CSF) signaling. G-CSF signaling leads to a signal cascade including the phosphorylation of Lyn kinase and STAT3. This in turn regulates expression of the neutrophil surface receptor chemokine receptor 2 (CXCR2) and causes translocation of the receptor into detergent-resistant membranes (DRMs). In this study we investigated the role of ceramides in G-CSF signaling. We found, that G-CSF treatment of wild type bone marrow cells (BMCs) leads to translocation of G-CSF-receptor (G-CSF-R) into DRMs. G-CSF also induces downregulation of ceramides in WT and CerS2 null BMCs, as well as upregulation of very long chain lactosylceramides. However, in CerS2 null BMCs, G-CSF failed to induce translocation of G-CSF-R into DRMs, leading to reduced phosphorylation of Lyn and reduced CXCR2 expression. Interestingly, G-CSF signaling in CerS6 null BMCs was not affected. In conclusion, very long chain ceramides are important for G-CSF signaling and translocation of G-CSF-R into DRMs.