Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism.
Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism.
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脂肪酸从头合成的遗传相互作用的系统图谱确定了 C12orf49 是脂质代谢的调节剂。
DOI：
10.1038/s42255-020-0211-z
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发表时间：
2020-06
影响因子：
20.8
通讯作者：
Moffat J
中科院分区：
文献类型：
--
作者：
Aregger M;Lawson KA;Billmann M;Costanzo M;Tong AHY;Chan K;Rahman M;Brown KR;Ross C;Usaj M;Nedyalkova L;Sizova O;Habsid A;Pawling J;Lin ZY;Abdouni H;Wong CJ;Weiss A;Mero P;Dennis JW;Gingras AC;Myers CL;Andrews BJ;Boone C;Moffat J
从头合成脂肪酸已成为包括癌症在内的各种疾病的治疗靶点。由于癌细胞本身具有抵抗代谢应激的缓冲能力，因此了解细胞如何适应新脂肪酸生物合成的丧失是很重要的。在这里，我们使用汇集的全基因组CRISPR筛选系统地绘制了携带FASN功能缺失突变的人类HAP1细胞的遗传相互作用（GIs），其产物催化长链脂肪酸的形成。FASN突变细胞表现出对脂质摄取的强烈依赖，这反映在与LDL受体途径、囊泡运输和蛋白质糖基化相关的基因的负GIs中。对这些功能关系的进一步支持来自于对其他参与脂质代谢的基因（包括LDLR、SREBF1、SREBF2、ACACA）缺乏的细胞系的额外GI筛选。我们的GI图谱还发现了先前未被表征的基因LUR1/C12orf49在脂质饥饿反应中通过调节SREBF2信号参与外源性脂质摄取调节的潜在作用。总的来说，我们的数据强调了与新脂肪酸合成损失相关的细胞适应的遗传决定因素，并证明了系统GI制图在揭示人类细胞代谢缓冲机制方面的力量。
The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. Since cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to loss of de novo fatty acid biosynthesis. Here we use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, whose product catalyzes the formation of long-chain fatty acids. FASN mutant cells show a strong dependence on lipid uptake that is reflected in negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene LUR1/C12orf49 in exogenous lipid uptake regulation through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.
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影响因子：
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