Increased long chain acyl-Coa synthetase activity and fatty acid import is linked to membrane synthesis for development of picornavirus replication organelles.
Increased long chain acyl-Coa synthetase activity and fatty acid import is linked to membrane synthesis for development of picornavirus replication organelles.
复制标题
DOI：
10.1371/journal.ppat.1003401
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Belov GA
中科院分区：
文献类型：
--
作者：
Nchoutmboube JA;Viktorova EG;Scott AJ;Ford LA;Pei Z;Watkins PA;Ernst RK;Belov GA
所有真核生物的正链(+RNA)病毒都是通过膜来复制它们的基因组。感染细胞膜重塑的机制为设计未来的治疗方法提供了诱人的靶点，但我们对这一过程的了解非常有限。自噬元件和/或分泌途径被认为是为了建立微小核糖核酸病毒复制细胞器而劫持的。然而，即使是密切相关的病毒对这些途径的组件的要求也有很大的不同。我们在这里证明，感染不同的小核糖核酸病毒会迅速激活长链脂肪酸的进口。而在未感染的细胞中，进口的脂肪酸被引导到脂滴中，而在感染的细胞中，中性脂的合成被关闭，脂肪酸被用于高度上调的磷脂酰胆碱合成。因此，复制细胞器很可能是用从头合成的膜材料建造的，而不是用改造后的预先存在的膜建造的。我们发现，脂肪酸输入的激活与细胞长链酰辅酶A合成酶活性的上调有关，并确定长链酰基辅酶A合成酶3(ACSL3)是脊髓灰质炎复制所需的一种新的宿主因子。需要脊髓灰质炎病毒蛋白2A来激活进口脂肪酸，而不依赖于其蛋白酶活性。感染细胞脂肪酸进口偏好的改变导致磷脂酰胆碱的合成不同于未感染细胞中的磷脂酰胆碱，认为病毒复制细胞器与先前存在的膜相比具有独特的性质。我们的数据表明，脊髓灰质炎病毒如何通过瞄准一个关键过程来改变整体细胞膜的动态平衡。他们解释了早期观察到的感染细胞磷脂合成增加的现象，并提出了一种简单的微微核糖核酸类病毒复制复合体膜支架结构发展的模型，这可能也与其他(+)RNA病毒有关。真核细胞具有惊人的调控网络的复杂性，但对这种微调机制的控制很容易被只表达少数蛋白质的病毒所超越。这种恶意接管的一个引人注目的例子是(+)RNA病毒重新连接正常的细胞膜新陈代谢，以发展含有病毒复制机制的新的膜细胞器。(+)真核生物的RNA病毒可感染从单细胞藻类到人类的生物。它们中的许多会引发疾病，造成重大经济损失、公共卫生负担、人类痛苦，有时还会造成致命后果。我们展示了微小核糖核酸病毒如何通过靶向长链酰辅酶A合成酶活性来重组细胞脂代谢。这导致感染细胞中的脂肪酸进口增加，磷脂合成上调，导致复制细胞器的形成不同于先前存在的细胞膜。这一机制被多种病毒利用，可能是抗病毒干预的一个有吸引力的靶点。
All positive strand (+RNA) viruses of eukaryotes replicate their genomes in association with membranes. The mechanisms of membrane remodeling in infected cells represent attractive targets for designing future therapeutics, but our understanding of this process is very limited. Elements of autophagy and/or the secretory pathway were proposed to be hijacked for building of picornavirus replication organelles. However, even closely related viruses differ significantly in their requirements for components of these pathways. We demonstrate here that infection with diverse picornaviruses rapidly activates import of long chain fatty acids. While in non-infected cells the imported fatty acids are channeled to lipid droplets, in infected cells the synthesis of neutral lipids is shut down and the fatty acids are utilized in highly up-regulated phosphatidylcholine synthesis. Thus the replication organelles are likely built from de novo synthesized membrane material, rather than from the remodeled pre-existing membranes. We show that activation of fatty acid import is linked to the up-regulation of cellular long chain acyl-CoA synthetase activity and identify the long chain acyl-CoA syntheatse3 (Acsl3) as a novel host factor required for polio replication. Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity. Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes. Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process. They explain earlier observations of increased phospholipid synthesis in infected cells and suggest a simple model of the structural development of the membranous scaffold of replication complexes of picorna-like viruses, that may be relevant for other (+)RNA viruses as well. Eukaryotic cells feature astonishing complexity of regulatory networks, yet control over this fine-tuned machinery is easily overrun by viruses with expression of just a handful of proteins. One of the striking examples of such hostile take-over is the rewiring of normal cellular membrane metabolism by (+)RNA viruses towards development of new membranous organelles harboring viral replication machinery. (+)RNA viruses of eukaryotes infect organisms from unicellular algae to humans. Many of them induce diseases resulting in significant economic losses, public health burden, human suffering and sometimes fatal consequences. We show how picornaviruses reorganize cellular lipid metabolism by targeting long chain acyl-CoA synthetase activity. This induces increased import of fatty acids in infected cells and up-regulation of phospholipid synthesis, resulting in formation of replication organelles different from the pre-existing cellular membranes. This mechanism is utilized by diverse viruses and may represent an attractive target for anti-viral interventions.
登录
查看更多内容
影响因子：
5.4
作者：
Belov, GA;Lidsky, PV;Agol, VI
通讯作者：
Agol, VI
影响因子：
4.8
作者：
Coe, NR;Smith, AJ;Bernlohr, DA
通讯作者：
Bernlohr, DA
影响因子：
6.7
作者：
Belov GA;Feng Q;Nikovics K;Jackson CL;Ehrenfeld E
通讯作者：
Ehrenfeld E
影响因子：
5.9
作者：
Belov GA;van Kuppeveld FJ
通讯作者：
van Kuppeveld FJ
影响因子：
3.7
作者：
CALIGUIRI, LA;TAMM, I
通讯作者：
TAMM, I