Human Cytomegalovirus Uses a Host Stress Response To Balance the Elongation of Saturated/Monounsaturated and Polyunsaturated Very-Long-Chain Fatty Acids

Abstract

Stress and virus infection regulate lipid metabolism. Human cytomegalovirus (HCMV) infection induces fatty acid (FA) elongation and increases the abundance of lipids with very-long-chain FA (VLCFA) tails. While reprogramming of metabolism can be stress related, the role of stress in HCMV reprogramming of lipid metabolism is poorly understood. In this study, we engineered cells to knock out protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) in the ER stress pathway and measured lipid changes using lipidomics to determine if PERK is needed for lipid changes associated with HCMV infection. In HCMV-infected cells, PERK promotes increases in the levels of phospholipids with saturated FA (SFA) and monounsaturated FA (MUFA) VLCFA tails. Further, PERK enhances FA elongase 7 (ELOVL7) protein levels, which elongates SFA and MUFA VLCFAs. Additionally, we found that increases in the elongation of polyunsaturated fatty acids (PUFAs) associated with HCMV infection were independent of PERK and that lipids with PUFA tails accumulated in HCMV-infected PERK knockout cells. Additionally, the protein levels of ELOVL5, which elongates PUFAs, are increased by HCMV infection through a PERK-independent mechanism. These observations show that PERK differentially regulates ELOVL7 and ELOVL5, creating a balance between the synthesis of lipids with SFA/MUFA tails and PUFA tails. Additionally, we found that PERK was necessary for virus replication and the infectivity of released viral progeny. Overall, our findings indicate that PERK—and, more broadly, ER stress—may be necessary for the membrane biogenesis needed to generate infectious HCMV virions. IMPORTANCE HCMV is a common herpesvirus that establishes lifelong persistent infections. While infection is asymptomatic in most people, HCMV causes life-threatening illnesses in immunocompromised people, including transplant recipients and cancer patients. Additionally, HCMV infection is a leading cause of congenital disabilities. HCMV replication relies on lipid synthesis. Here, we demonstrated that the ER stress mediator PERK controls FA elongation and the cellular abundance of several types of lipids following HCMV infection. Specifically, PERK promotes FA elongase 7 synthesis and phospholipids with saturated/monounsaturated very-long-chain FA tails. Overall, our study shows that PERK is an essential host factor that supports HCMV replication and promotes lipidome changes caused by HCMV infection.

Viral Infection Drives the Regulation of Feeding Behavior Related Genes in Salmo salar

“…This endoplasmic reticulum-bound enzymatic process allows two carbons to the chain of long- and very-long-chain fatty acids (VLCFAs) per cycle. Elov 5 is also highly involved in the elongation of long-chain polyunsaturated fatty acids such as C18 and C20 PUFA [ 54 ]. It has been observed that under virus infection, Elov2, and specifically, Elov5, are highly activated and overregulate lipid metabolism.…”

“…It has been observed that under virus infection, Elov2, and specifically, Elov5, are highly activated and overregulate lipid metabolism. For example, the human cytomegalovirus (HCMV) infection induces fatty acid (FA) elongation and increases the abundance of lipids with very long-chain FA (VLCFA) tails by the activation of the Elov2 and Elov5 [ 54 ]. Specifically, it has been observed that the virus impacts the protein levels of ELOVL5, which elongates PUFAs through a PERK-independent mechanism.…”

The p97-UBXD8 complex modulates ER-Mitochondria contact sites by modulating membrane lipid saturation and composition

“…Lipids were identified and quantitatively measured using ultra high-performance liquid- chromatography high-resolution tandem MS/MS (UHPLC-MS/MS) as recently described 69, 70 . Separation of lipids was done by reverse-phase chromatography using a Kinetex 2.6 µm C18 column (Phenomenex 00F-4462-AN) at 60°C using a Vanquish UHPLC system (Thermo Scientific) and two solvents: solvent A (40:60 water-methanol plus 10mM ammonium formate and 0.1% formic acid) and solvent B (10:90 methanol-isopropanol plus 10mM ammonium formate and 0.1% formic acid).…”

“…Lipids were identified and quantitatively measured using ultra high-performance liquidchromatography high-resolution tandem MS/MS (UHPLC-MS/MS) as recently described 69,70 .…”

Oncolytic Virus-Induced Autophagy in Glioblastoma

“…ER stress is often developed as a secondary mechanism to drug treatment or viral persistence. This is the case with HCMV [ 42 ], the hepatitis C virus [ 43 ], and the hepatitis B virus [ 44 ]. The infection of normal brain cells [ 45 , 46 ] and/or glioma cells [ 47 , 48 ] with retroviruses, NDV, or MDA-7/IL-24 also leads to ER modifications in cellular programming.…”