Liu Li-Ka, Choudhary Vineet, Toulmay Alexandre, Prinz William A
Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
J Cell Biol. 2017 Jan 2;216(1):131-147. doi: 10.1083/jcb.201606059. Epub 2016 Dec 23.
Ceramides are key intermediates in sphingolipid biosynthesis and potent signaling molecules. However, excess ceramide is toxic, causing growth arrest and apoptosis. In this study, we identify a novel mechanism by which cells prevent the toxic accumulation of ceramides; they facilitate nonvesicular ceramide transfer from the endoplasmic reticulum (ER) to the Golgi complex, where ceramides are converted to complex sphingolipids. We find that the yeast protein Nvj2p promotes the nonvesicular transfer of ceramides from the ER to the Golgi complex. The protein is a tether that generates close contacts between these compartments and may directly transport ceramide. Nvj2p normally resides at contacts between the ER and other organelles, but during ER stress, it relocalizes to and increases ER-Golgi contacts. ER-Golgi contacts fail to form during ER stress in cells lacking Nvj2p. Our findings demonstrate that cells regulate ER-Golgi contacts in response to stress and reveal that nonvesicular ceramide transfer out of the ER prevents the buildup of toxic amounts of ceramides.
神经酰胺是鞘脂生物合成的关键中间体和强效信号分子。然而，过量的神经酰胺具有毒性，会导致生长停滞和细胞凋亡。在本研究中，我们确定了一种细胞防止神经酰胺毒性积累的新机制；它们促进神经酰胺从内质网（ER）到高尔基体复合体的非囊泡转运，在高尔基体复合体中神经酰胺被转化为复合鞘脂。我们发现酵母蛋白Nvj2p促进神经酰胺从内质网到高尔基体复合体的非囊泡转运。该蛋白是一种系链，在这些区室之间产生紧密接触，并且可能直接运输神经酰胺。Nvj2p通常位于内质网与其他细胞器之间的接触点，但在内质网应激期间，它重新定位并增加内质网 - 高尔基体接触。在缺乏Nvj2p的细胞中，内质网应激期间内质网 - 高尔基体接触无法形成。我们的研究结果表明，细胞响应应激调节内质网 - 高尔基体接触，并揭示从内质网输出的非囊泡神经酰胺转运可防止毒性量的神经酰胺积累。
