Investigating the Role of Lysine Lactylation during Human Cytomegalovirus Infection

Abstract

Post-translational modifications (PTMs) regulate diverse cellular pathways through modulation of protein function. Previous studies have shown that certain PTMs are derived from crucial cellular metabolites, and dysregulation of these PTMs contributes to diseases such as cancer and infectious diseases. Human cytomegalovirus (HCMV), a type 5 β-herpesvirus, causes life-threatening illnesses for newborns and immunocompromised individuals. HCMV infection is characterized by an upregulation of glycolytic activity and lactate production, and the Cristea Lab recently discovered that lysine lactylation – a PTM derived from lactate – is dynamically and temporally regulated during HCMV infection. Lactylation promotes an anti-inflammatory state in immune cells and the lactate-rich tumor microenvironment; however, the function of lactylation during viral infections has not been studied. Using molecular virology and proteomics techniques, this study investigates how lysine lactylation influences the immune response to viral infection. This study shows that globally, increasing lactylation is not sufficient to affect the immune response. Yet, lactylation of specific, evolutionarily conserved lysines on the RBM14 and HEXIM1 proteins of the HDP-RNP complex inhibit the immune response and aid HCMV replication. Finally, this study finds evidence suggesting the HDP-RNP complex coordinates with IFI16, a viral DNA sensor, to regulate immune signaling. Taken together, the findings from this study provide insight into the importance of increased lactate production during herpesvirus infections, and highlights lactylation as a tool for modulating host immune responses to viral infections.