Human Cytomegalovirus Remodeling of Lipid Metabolism Requires pUL37x1

Human cytomegalovirus (HCMV) replication requires remodeling of the host metabolic network, including increasing central carbon metabolism, fatty acid elongation and lipid synthesis. The virus-host interactions regulating HCMV metabolic hijacking are essential to infection. While multiple host factors including kinases and transcription factors have been defined, little is known about the viral factors required. Some host factors involved are dependent on Ca2+ signaling or host stress response. The viral pUL37x1 protein mobilizes Ca2+ and targets the mitochondria. The Ca2+ changes induced by pUL37x1 can activate stress responses. In this study, we tested the hypothesis that the viral pUL37x1 protein is required for HCMV metabolic remodeling. Using a combination of metabolomics, lipidomics, and metabolic tracers, we demonstrate that pUL37x1 protein is necessary for HCMV induced fatty acid elongation and lipid metabolism but not required for most viral hijacking of central carbon metabolism. Additionally, we show that pUL37x1 is required for HCMV to fully induce two host proteins that were previously demonstrated to be important for virus induced lipid metabolism: fatty acid elongase 7 and the ER-stress related kinase PERK. We also demonstrate, for the first time, that HCMV replication results in the increase in phospholipids with very-long chain fatty acyl tails. We conclude that pUL37x1 is required for HCMV metabolic remodeling but is not necessary to for the virus to hijack metabolism on a network-wide scale.