Long-term autophagy is sustained by activation of CCTβ3 on lipid droplets
Long-term autophagy is sustained by activation of CCTβ3 on lipid droplets
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DOI：
10.1038/s41467-020-18153-w
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发表时间：
2020-09-08
影响因子：
16.6
通讯作者：
Fujimoto, Toyoshi
中科院分区：
文献类型：
--
作者：
Ogasawara, Yuta;Cheng, Jinglei;Fujimoto, Toyoshi
巨噬通过形成隔离膜而开始，但膜生物发生的磷脂来源仍不清楚。在这里，我们发现自噬膜结合了新合成的磷脂酰胆碱，并且CTP：磷脂酰转移酶β 3 (CCT β 3)，肯尼迪途径中限速酶的一种亚型，起着至关重要的作用。在饥饿的小鼠胚胎成纤维细胞中，CCT β 3最初被招募到自噬膜上，但在长期饥饿后，它集中在自噬降解产物产生的脂滴上。脂滴周围散发出omega - asome和隔离膜。长期饥饿中的自噬可通过下调CCT β 3而受到抑制，并通过其过表达而增强。这种依赖CCT β 3的机制也存在于骨肉瘤细胞系U2OS中，缺乏CCT β 3会降低饥饿状态下的自噬和细胞存活。结果表明，脂滴上CCT β 3激活的磷脂酰胆碱合成对于维持自噬和细胞的长期存活至关重要。
Macroautophagy initiates by formation of isolation membranes, but the source of phospholipids for the membrane biogenesis remains elusive. Here, we show that autophagic membranes incorporate newly synthesized phosphatidylcholine, and that CTP:phosphocholine cytidylyltransferase beta 3 (CCT beta 3), an isoform of the rate-limiting enzyme in the Kennedy pathway, plays an essential role. In starved mouse embryo fibroblasts, CCT beta 3 is initially recruited to autophagic membranes, but upon prolonged starvation, it concentrates on lipid droplets that are generated from autophagic degradation products. Omegasomes and isolation membranes emanate from around those lipid droplets. Autophagy in prolonged starvation is suppressed by knockdown of CCT beta 3 and is enhanced by its overexpression. This CCT beta 3-dependent mechanism is also present in U2OS, an osteosarcoma cell line, and autophagy and cell survival in starvation are decreased by CCT beta 3 depletion. The results demonstrate that phosphatidylcholine synthesis through CCT beta 3 activation on lipid droplets is crucial for sustaining autophagy and long-term cell survival.