FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication.
FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication.
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DOI：
10.1016/j.chembiol.2021.07.022
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发表时间：
2022-05-19
影响因子：
8.6
通讯作者：
Ichi I
中科院分区：
文献类型：
--
作者：
Yamane D;Hayashi Y;Matsumoto M;Nakanishi H;Imagawa H;Kohara M;Lemon SM;Ichi I
细胞脂质的代谢氧化降解严重限制了慢性肝病的主要原因丙型肝炎病毒（HCV）的复制，但对受感染细胞中调节这一过程的因素知之甚少。在这里，我们表明，丙型肝炎病毒是由一个铁依赖性机制的限制，类似于一个触发铁凋亡，铁依赖性形式的非凋亡性细胞死亡，并介导的非典型的去饱和油酸米德酸和其他高度不饱和脂肪酸的脂肪酸去饱和酶2（FADS 2）。遗传耗竭和异位表达实验表明FADS 2是细胞对铁凋亡敏感性的关键决定因素。抑制FADS2显著增强HCV复制，而亚铁凋亡诱导化合物erastin改变HCV复制酶的构象，并使其对靶向病毒蛋白酶的直接作用的抗病毒剂敏感。我们的研究结果确定FADS2作为铁凋亡的限速因子，并提出了操纵铁凋亡途径来减弱病毒复制的可能性。Yamane等人证明，调节铁凋亡的细胞代谢过程非细胞溶解性地限制了丙型肝炎病毒在肝细胞中的复制。作者表明，铁中毒样信号主要受FADS 2催化的典型和非典型脂肪酸去饱和和高度不饱和脂肪酸的铁依赖性氧化的调节。
The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is known about the factors regulating this process in infected cells. Here we show that HCV is restricted by an iron-dependent mechanism resembling the one triggering ferroptosis, an iron-dependent form of non-apoptotic cell death, and mediated by the non-canonical desaturation of oleate to Mead acid and other highly unsaturated fatty acids by fatty acid desaturase 2 (FADS2). Genetic depletion and ectopic expression experiments show FADS2 is a key determinant of cellular sensitivity to ferroptosis. Inhibiting FADS2 markedly enhances HCV replication, whereas the ferroptosis-inducing compound erastin alters conformation of the HCV replicase and sensitizes it to direct-acting antiviral agents targeting the viral protease. Our results identify FADS2 as a rate-limiting factor in ferroptosis, and suggest the possibility of pharmacologically manipulating the ferroptosis pathway to attenuate viral replication. Yamane et al. demonstrate that cellular metabolic processes that regulate ferroptosis noncytolytically restrict replication of hepatitis C virus in hepatocytes. The authors show that the ferroptosis-like signals are regulated primarily by canonical and non-canonical fatty acid desaturation catalyzed by FADS2 and iron-dependent oxidation of highly-unsaturated fatty acids.
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