Dataset Information

Global Lysine Lactylation Dynamics during HCMV and HSV-1 Infections

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 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.

INSTRUMENT(S): timsTOF Ultra, Q Exactive HF

ORGANISM(S): Homo Sapiens (human) Human Alphaherpesvirus 1 Human Cytomegalovirus (hhv-5) (human Herpesvirus 5)

TISSUE(S): Lung Fibroblast Cell Line, Fibroblast

DISEASE(S): Herpes Simplex,Human Cytomegalovirus Infection

SUBMITTER: Matthew Tyl

LAB HEAD: Ileana Cristea

PROVIDER: PXD055230 | Pride | 2024-11-23

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	HSV1_LaIP_DIA_RF-HSV1.d.zip	Other
	HSV1_LaIP_DIA_WT-HSV1.d.zip	Other
	HSV1_LaIP_DIA_mock.d.zip	Other
	HSV1_WP_DIA_RF-HSV1.d.zip	Other
	HSV1_WP_DIA_WT-HSV1.d.zip	Other

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Publications

Infection-induced lysine lactylation enables herpesvirus immune evasion.

Tyl Matthew D MD Merengwa Victoria U VU Cristea Ileana M IM

Science advances 20250108 2

Aerobic glycolysis is a hallmark of many viral infections, leading to substantial accumulation of lactate. However, the regulatory roles of lactate during viral infections remain poorly understood. Here, we report that human cytomegalovirus (HCMV) infection leverages lactate to induce widespread protein lactylation and promote viral spread. We establish that lactyllysine is enriched in intrinsically disordered regions, regulating viral protein condensates and immune signaling transduction. Dynam ...[more]

PMID: 39772686

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Project description:Rapid and dynamically shifting protein-protein interactions (PPIs) underlie the capacity of cells to recognize viral infections and ignite the downstream cascades that constitute the innate-immune response. Herpesviruses share an ancient history of coevolution with their hosts and have developed reciprocal methods to suppress or hijack immune response proteins — underscoring the biological complexity of host-pathogen interactions during the immune response. Accordingly, conventional approaches to studying PPIs downstream of innate immune sensing fail to capture both the global scope and the dynamic on-off behavior of protein complexes as they are altered throughout cellular space and time. To overcome this barrier, we have applied Thermal Proteome Profiling Mass Spectrometry (TPP-MS) to systemically characterize PPIs that coordinate the innate-immune response to Herpes Simplex Virus 1 (HSV-1) infection in primary human fibroblasts. Further, by advancing the power of thermal protein co ggregation analysis (TPCA) to infer associations de novo and to globally track these PPIs, we developed a time-resolved portrait of cellular and viral protein associations with IFI16, a nuclear DNA sensor that serves as a central platform for HSV-1 immune responses. Our TPCA analysis, along with high-resolution microscopy and molecular virological techniques, linked IFI16 sensing of viral DNA in the nuclear periphery to the master DNA damage response (DDR) regulatory kinase, DNA-PK — the activation of which we show to be necessary for the antiviral and inflammatory responses to infection. Finally, phospho-peptide enrichment and MS analysis of DNA-PK substrates revealed IFI16 to be targeted by DNA-PK after both DNA damage and viral infection. Functional analysis of this DDR-dependent IFI16 phosphorylation revealed the specific modified residue required for IFI16-driven cytokine responses. Altogether, our study represents the first systems-wide characterization of the global dynamics of PPIs during HSV-1 infection and uncovers a missing link in the immune signaling pathway that places IFI16 and DNA-PK at the center of herpesvirus innate immunity.