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Nature:“神经酰胺-1-磷酸盐”的细胞输送

  1. 神经酰胺-1-磷酸盐丨细胞输送

来源:Nature 2013-08-22 18:54

具有生物活性的信号作用脂质“神经酰胺-1-磷酸盐”(C1P) 调控从生长和生存到“促炎反应”在内的各种不同过程。在这项研究中,Dinshaw Patel及同事研究了C1P是怎样被输送到细胞中的特定点的。他们识别出被称为“神经酰胺-1-磷酸盐转移蛋白”(CPTP)的一种新颖的脂质转移蛋白,同时结构和功能研究也显示了C1P被从其在“高尔基”复合体中的合成点输送到胞质膜上的机制。

具有生物活性的信号作用脂质“神经酰胺-1-磷酸盐”(C1P) 调控从生长和生存到“促炎反应”在内的各种不同过程。在这项研究中,Dinshaw Patel及同事研究了C1P是怎样被输送到细胞中的特定点的。他们识别出被称为“神经酰胺-1-磷酸盐转移蛋白”(CPTP)的一种新颖的脂质转移蛋白,同时结构和功能研究也显示了C1P被从其在“高尔基”复合体中的合成点输送到胞质膜上的机制。(生物谷Bioon.com)

生物谷推荐英文摘要:

Nature               doi: 10.1038/nature12332

Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids

Dhirendra K. Simanshu, Ravi Kanth Kamlekar, Dayanjan S. Wijesinghe, Xianqiong Zou, Xiuhong Zhai, Shrawan K. Mishra, Julian G. Molotkovsky  Lucy Malinina, Edward H. Hinchcliffe, Charles E. Chalfant, Rhoderick E. Brown, Dinshaw J. Patel

Phosphorylated sphingolipids ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation. C1P produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2α (cPLA2α), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma or airway hyper-responsiveness, cancer, atherosclerosis and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. Vesicular trafficking is likely but non-vesicular mechanisms for C1P sensing, transfer and presentation remain unexplored. Moreover, the molecular basis for selective recognition and binding among signalling lipids with phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, α-helically-dominated ‘sandwich’ topology identifies CPTP as the prototype for a new glycolipid transfer protein fold13 subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi network, nucleus and plasma membrane. RNA interference-induced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2α release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.

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