Martin Madison, Kumar Rinki, Buchkovich Nicholas J, Norbury Christopher C
Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, Pennsylvania, USA.
J Virol. 2025 Feb 25;99(2):e0185124. doi: 10.1128/jvi.01851-24. Epub 2025 Jan 7.
Human cytomegalovirus (HCMV) modulates numerous cellular pathways to facilitate infection, including key components in cellular iron homeostasis. Iron is essential to many cellular processes but, if present in excess, drives cell death through ferroptosis. Ferroptosis is a process that is dependent upon the accumulation of oxidatively damaged phospholipids (lipid peroxides); when these lipid peroxides accumulate in membranes, this culminates in plasma membrane rupture and eventual cell lysis. Here, we demonstrate that HCMV infection downregulates the expression of a key modulator of lipid peroxidation, glutathione peroxidase 4 (GPX4). HCMV infection also markedly increased levels of lipid peroxides within infected cells. Despite the marked downregulation of GPX4 by HCMV, further inhibition of GPX4 impaired virus replication. Interestingly, overexpression of GPX4 did not reduce the production of lipid peroxides within infected cells. In contrast, lipid peroxide levels were reduced by treatment with ferrostatin-1, a ferrous iron-dependent scavenger of alkoxyl radicals, indicating a role for iron in the production of lipid peroxides. HCMV-infected cells became less sensitive to GPX4 inhibition as infection progressed, requiring substantially higher levels of GPX4 inhibitors to induce ferroptosis compared to uninfected cells. This observed difference in sensitivity to ferroptosis upon infection correlated with a large increase in lipid production by infected cells. Therefore, the marked stimulation of lipid peroxidation by HCMV likely proceeds through a pathway that is independent of GPX4 regulation, but the ability of lipid peroxides to stimulate ferroptosis by modulating plasma membrane rupture is likely blunted by the massive increase in lipid production during HCMV infection.
Human cytomegalovirus (HCMV) infection is intimately linked with countless host cell pathways that are modulated in a coordinated fashion to facilitate infection. Here, we describe HCMV-induced regulation of lipid peroxidation, a precursor of the iron-regulated cell death pathway known as ferroptosis, during human cytomegalovirus infection. These studies reveal hitherto unidentified changes in metabolism mediated by HCMV that decrease sensitivity to ferroptosis, despite increases in lipid peroxidation and transient increases in intracellular iron levels in infected cells.
人巨细胞病毒（HCMV）可调节众多细胞途径以促进感染，包括细胞铁稳态的关键成分。铁对许多细胞过程至关重要，但如果过量存在，会通过铁死亡驱动细胞死亡。铁死亡是一个依赖于氧化损伤磷脂（脂质过氧化物）积累的过程；当这些脂质过氧化物在膜中积累时，最终会导致质膜破裂和细胞最终裂解。在这里，我们证明HCMV感染下调脂质过氧化的关键调节因子谷胱甘肽过氧化物酶4（GPX4）的表达。HCMV感染还显著增加了感染细胞内脂质过氧化物的水平。尽管HCMV显著下调了GPX4，但进一步抑制GPX4会损害病毒复制。有趣的是，GPX4的过表达并未降低感染细胞内脂质过氧化物的产生。相反，用铁抑素-1（一种亚铁离子依赖性烷氧基自由基清除剂）处理可降低脂质过氧化物水平，表明铁在脂质过氧化物产生中起作用。随着感染的进展，HCMV感染的细胞对GPX4抑制的敏感性降低，与未感染细胞相比，诱导铁死亡需要高得多水平的GPX4抑制剂。观察到的感染后对铁死亡敏感性的差异与感染细胞脂质产生的大量增加相关。因此，HCMV对脂质过氧化的显著刺激可能通过一条独立于GPX4调节的途径进行，但在HCMV感染期间，脂质过氧化物通过调节质膜破裂刺激铁死亡的能力可能因脂质产生的大量增加而减弱。
人巨细胞病毒（HCMV）感染与无数宿主细胞途径密切相关，这些途径以协调的方式被调节以促进感染。在这里，我们描述了在人巨细胞病毒感染期间，HCMV诱导的脂质过氧化调节，脂质过氧化是铁调节的细胞死亡途径铁死亡的前体。这些研究揭示了HCMV介导的代谢中迄今未被识别的变化，尽管感染细胞中脂质过氧化增加且细胞内铁水平短暂升高，但这些变化降低了对铁死亡的敏感性。
