Nuclear-localized CTP:phosphocholine cytidylyltransferase α regulates phosphatidylcholine synthesis required for lipid droplet biogenesis.
Nuclear-localized CTP:phosphocholine cytidylyltransferase α regulates phosphatidylcholine synthesis required for lipid droplet biogenesis.
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DOI：
10.1091/mbc.e15-03-0159
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发表时间：
2015-08-15
影响因子：
3.3
通讯作者：
Ridgway ND
中科院分区：
文献类型：
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作者：
Aitchison AJ;Arsenault DJ;Ridgway ND
哺乳动物细胞通过CDP-胆碱途径合成磷脂酰胆碱(PC)，调节脂滴大小和三酰甘油的储存。从机制上讲，这涉及到cctα表达的增加和核膜的易位。Cctα调节脂滴生物发生所需的PC合成，而不与颗粒表面结合。CTP：磷酸胆碱胞苷转移酶α(Cctα)与细胞膜的可逆结合通过CdP-胆碱(肯尼迪)途径调节磷脂酰胆碱(PC)的合成。根据与昆虫cct同源物的结果，核cctα移位到细胞质脂滴上，以刺激细胞质脂滴生物发生和三酰甘油(TAG)储存所需的PC的合成。我们检查了这种调控机制是否适用于哺乳动物细胞中的LD生物发生。在3T3-L1和人前脂肪细胞分化过程中，Cctα表达和PC合成被诱导。在3T3-L1细胞中，Cctα从核浆转位到核膜和胞浆，但与LDS无关。在人类脂肪细胞分化过程中，这种酶也保留在细胞核中。在3T3-L1细胞中的RNA干扰沉默表明，Cctα调节LD的大小，但不影响标签的储存或脂肪的形成。油酸处理的非脂肪细胞系的LD生物发生也促进了Cctα移位到核膜和/或细胞质，但不促进LDs。在大鼠肠上皮细胞中，Cctα沉默增加了LD的大小，但由于油酸诱导的细胞毒性，LD的数量和Tag的沉积减少。我们得出结论，CCTα通过移位到核膜而不是细胞质LD来增加LD生物发生的PC合成。
Phosphatidylcholine (PC) synthesis by the CDP-choline pathway in mammalian cells regulates lipid droplet size and triacylglycerol storage. Mechanistically this involves increased CCTα expression and translocation to the nuclear envelope. CCTα regulates the PC synthesis required for lipid droplet biogenesis without associating with the surface of the particle. The reversible association of CTP:phosphocholine cytidylyltransferase α (CCTα) with membranes regulates the synthesis of phosphatidylcholine (PC) by the CDP-choline (Kennedy) pathway. Based on results with insect CCT homologues, translocation of nuclear CCTα onto cytoplasmic lipid droplets (LDs) is proposed to stimulate the synthesis of PC that is required for LD biogenesis and triacylglycerol (TAG) storage. We examined whether this regulatory mechanism applied to LD biogenesis in mammalian cells. During 3T3-L1 and human preadipocyte differentiation, CCTα expression and PC synthesis was induced. In 3T3-L1 cells, CCTα translocated from the nucleoplasm to the nuclear envelope and cytosol but did not associate with LDs. The enzyme also remained in the nucleus during human adipocyte differentiation. RNAi silencing in 3T3-L1 cells showed that CCTα regulated LD size but did not affect TAG storage or adipogenesis. LD biogenesis in nonadipocyte cell lines treated with oleate also promoted CCTα translocation to the nuclear envelope and/or cytoplasm but not LDs. In rat intestinal epithelial cells, CCTα silencing increased LD size, but LD number and TAG deposition were decreased due to oleate-induced cytotoxicity. We conclude that CCTα increases PC synthesis for LD biogenesis by translocation to the nuclear envelope and not cytoplasmic LDs.