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Regulation of Global Lysine Lactylation during HCMV Infection

ABSTRACT: Aerobic glycolysis is a hallmark of virus-infected cells, leading to substantial accumulation and secretion of lactate. However, the regulatory roles of lactate during viral infections are still poorly understood. Here, we report that human cytomegalovirus (HCMV) infection leverages lactate to induce widespread protein lactylation and promote viral spread. Lactyllysine decorates intrinsically disordered regions (IDRs) of proteins, regulating viral protein condensates and immune signaling transduction. Dynamic lactylation of immune response pathways, a feature shared during infection with herpes simplex virus 1 (HSV-1), suppresses immunity through regulation of RBM14 and IFI16. K90 lactylation of the viral DNA sensor IFI16 blocks recruitment of the DNA-damage response master kinase DNA-PK, preventing IFI16-driven gene repression and cytokine responses. Together, we characterize global protein lactylation dynamics during virus infection, finding virus-induced lactate contributes to its immune evasion through direct inhibition of immune signaling pathways.

INSTRUMENT(S): timsTOF Ultra

ORGANISM(S): Cytomegalovirus Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Matthew Tyl

LAB HEAD: Ileana Cristea

PROVIDER: PXD057709 | Pride | 2024-11-23

REPOSITORIES: Pride

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			Action	DRS
	20241031_LaIP_96hpi_0mM.d.zip	Other
	20241031_LaIP_96hpi_alanine.d.zip	Other
	20241031_LaIP_96hpi_shAARS1.d.zip	Other
	20241031_LaIP_96hpi_shScr.d.zip	Other
	20241031_WP_96hpi_0mM.d.zip	Other

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Global Lysine Lactylation Dynamics during HCMV and HSV-1 Infections

Project description:Aerobic glycolysis is a hallmark of virus-infected cells, leading to substantial accumulation and secretion of lactate. However, the regulatory roles of lactate during viral infections are still poorly understood. Here, we report that human cytomegalovirus (HCMV) infection leverages lactate to induce widespread protein lactylation and promote viral spread. Lactyllysine decorates intrinsically disordered regions (IDRs) of proteins, regulating viral protein condensates and immune signaling transduction. Dynamic lactylation of immune response pathways, a feature shared during infection with herpes simplex virus 1 (HSV-1), suppresses immunity through regulation of HEXIM1, RBM14, and IFI16. K90 lactylation of the viral DNA sensor IFI16 blocks recruitment of the DNA-damage response master kinase DNA-PK, preventing IFI16-driven gene repression and cytokine responses. Together, we characterize global protein lactylation dynamics during virus infection, finding virus-induced lactate contributes to its immune evasion through direct inhibition of immune signaling pathways.

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IFI16 functions as an antiviral factor during influenza virus infection by binding viral RNA and enhancing the RIG-I signaling (RNA-seq)

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