Mechanisms of Human Cytomegalovirus Reprogramming of Lipid Metabolism

人类巨细胞病毒重编程脂质代谢的机制

• 批准号: 10656249
• 负责人: John Gerard Purdy
• 金额: $ 36.89万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656249
• 关键词: Address; Binding; Biochemical Pathway; Biological; Biological Process; Biology; CRISPR/Cas technology; Cells; Cessation of life; Cytomegalovirus; Cytomegalovirus Infections; Data; Dietary Intervention; Disease; Ensure; Environment; Enzymes; FRAP1 gene; Foundations; Glycoproteins; Goals; Herpesviridae; Human; Immunocompromised Host; Infection; Integration Host Factors; Knock-out; Knowledge; Lecithin; Life; Lipids; Membrane; Metabolic; Metabolism; Modeling; Molecular; Newborn Infant; Phospholipids; Positioning Attribute; Proteins; Public Health; Research; Role; Signal Pathway; Signal Transduction; Stress; Tail; Testing; Very Long Chain Fatty Acid; Viral; Virus; Virus Replication; Work; biological adaptation to stress; disability; experience; lipid biosynthesis; lipid metabolism; lipidome; lipidomics; mutant; novel; programs; receptor; response; small molecule; virus host interaction

PROJECT SUMMARY Human cytomegalovirus (HCMV) is a herpesvirus that causes disease and death in the immunocompromised and is a leading cause of congenital disabilities. HCMV replication requires lipids. Since HCMV does not encode a metabolic network, virus replication depends on host lipid metabolism. However, little is known about how HCMV reprograms host metabolism to ensure lipids required for virus replication are made. Our overall goal is to understand the virus-host interactions that regulate lipid synthesis essential for HCMV replication. Recently, we showed that HCMV infection results in an increase in lipid synthesis and a rise in lipid abundances. Here we demonstrate that HCMV infection induces the synthesis of at least 20 previously undescribed lipids unique to infected cells. Most of these unique lipids are phospholipids with very long-chain fatty acid tails (PL-VLCFAs). The PL-VLCFAs discussed in this application are understudied in general and unstudied in HCMV biology beyond our work. While shorter FA tails have been well-studied, we know little about lipids with VLCFAs tails that are as long as those we observe in HCMV infection, including how they will behave in a biological membrane. The molecular mechanisms underlying this HCMV-induced expansion in the host lipidome and the functional roles of the newly generated lipids are largely unknown. We discovered that HCMV pUL37x1 and pUL38 proteins promote PL-VLCFA synthesis, laying the foundation for understanding the mechanisms by which HCMV reprograms lipid synthesis. pUL37x1 and pUL38 induce Ca2+ and mTOR signaling, respectively. We have preliminary data suggesting that stress responses related to these signaling pathways contribute to HCMV remodeling of lipids. We hypothesize that pUL37x1 and pUL38 use Ca2+ and mTOR signaling to promote the synthesis of PC-VLCFAs required for HCMV replication. We will test this hypothesis by determining the mechanisms by which pUL37x1 and pUL38 promote synthesis of PL-VLCFAs (Aim 1) and defining the PL-VLCFA synthesis enzymes required for HCMV replication and the role of PL-VLCFAs in infection (Aim 2). These studies will determine the mechanisms by which HCMV interacts with the host to create a unique lipid environment advancing our knowledge of HCMV reprogramming of metabolism. Furthermore, these studies will define the biological functions of PC-VLCFAs in HCMV replication and further our understanding of lipids required for HCMV infection. Determining the mechanisms involved in HCMV-induced reprogramming of lipid metabolism and functions of PC-VLCFAs will advance knowledge in HCMV biology needed to identify new targets for treating infection.

项目摘要 人类巨细胞病毒（HCMV）是导致疾病和死亡的疱疹病毒 免疫功能低下，是先天性残疾的主要原因。 HCMV复制需要脂质。 由于HCMV不编码代谢网络，因此病毒复制取决于宿主脂质代谢。 但是，关于HCMV如何重新编程宿主代谢以确保病毒所需的脂质知之甚少 复制。我们的总体目标是了解调节脂质合成的病毒宿主相互作用 对于HCMV复制至关重要。最近，我们表明HCMV感染导致脂质增加 合成和脂质丰度的增加。在这里，我们证明HCMV感染诱导了合成 至少有20个以前未描述的脂质是被感染细胞独有的。这些独特的脂质中的大多数是磷脂 具有非常长链脂肪酸尾巴（PL-VLCFA）。本应用程序中讨论的PL-VLCFA是 在我们的工作之外，总体研究了HCMV生物学的研究。而较短的fa尾巴已经 经过充分研究，我们对带有VLCFAS尾巴的脂质几乎不懂，而Vlcfas尾巴与我们在HCMV中观察到的脂质相比 感染，包括它们在生物膜上的表现。这是基础的分子机制 HCMV诱导的宿主脂肪组中的扩张和新生成的脂质的功能作用是 在很大程度上未知。 我们发现HCMV PUL37X1和PUL38蛋白促进了PL-VLCFA合成，铺设了 理解HCMV重编程脂质合成的机制的基础。 PUL37x1和 PUL38分别诱导Ca2+和MTOR信号传导。我们有初步数据表明压力 与这些信号通路有关的响应有助于脂质的HCMV重塑。我们假设这一点 PUL37X1和PUL38使用Ca2+和MTOR信号传导来促进PC-VLCFA的合成 HCMV复制。我们将通过确定PUL37x1和PUL38的机制来检验这一假设 促进PL-VLCFAS的合成（AIM 1），并定义HCMV所需的PL-VLCFA合成酶 复制和PL-VLCFA在感染中的作用（AIM 2）。这些研究将通过 HCMV与宿主互动以创建一个独特的脂质环境，以推动我们对HCMV的了解 重新编程代谢。此外，这些研究将定义PC-VLCFA的生物学功能 在HCMV复制中，进一步了解了HCMV感染所需的脂质。确定 涉及HCMV引起的脂质代谢的重编程和PC-VLCFA功能的机制将 需要确定治疗感染的新靶标需要的HCMV生物学知识。

项目成果

IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection.

• DOI: 10.1128/mbio.00435-22
• 发表时间: 2022-06-28
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Griffante, Gloria;Hewelt-Belka, Weronika;Albano, Camilla;Gugliesi, Francesca;Pasquero, Selina;Castillo Pacheco, Sergio Fernando;Bajetto, Greta;Porporato, Paolo Ettore;Mina, Erica;Vallino, Marta;Krapp, Christian;Jakobsen, Martin Roelsgaard;Purdy, John;von Einem, Jens;Landolfo, Santo;Dell'Oste, Valentina;Biolatti, Matteo
• 通讯作者: Biolatti, Matteo