Lactylation: a Passing Fad or the Future of Posttranslational Modification

Qi, Xin; Wang, Hai; Li, Qinglin; Liu, Sinan; Qu, Kai; Liu, Chang; Zhang, Jingyao

doi:10.1007/s10753-022-01637-w

Cited by 41 publications

(25 citation statements)

References 78 publications

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“…Miar and colleagues reported a minimal role for HIF-1α or HIF-2α in regulating the hypoxic suppression of ISGs in cancer cell lines, but decreased chromatin accessibility of genomic regions relevant for type I IFN pathways (Miar et al 2020). Recent studies reported that lactate, a glycolytic product that is increased during hypoxia, regulates gene transcription via lactylation of histones (Xin et al 2022, Zhang, Tang, et al 2019). In tumor-infiltrating myeloid cells H3K18 lactylation increased N6-adenosine-methyltransferase 70 kDa subunit ( Mettl3 ) expression that modified Jak1 mRNA, thereby strengthening the immunosuppressive functions (Xiong et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia dampens innate immune signalling at early time points and increases Zika virus replication in iPSC-derived macrophages

Schilling

Vaughan-Jackson

James

et al. 2023

Preprint

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Type I interferons (IFNs) are the major host defence against viral infection and are induced following activation of cell surface or intracellular pattern recognition receptors, including retinoic-acid-inducible gene I (RIGI)-like receptors (RLRs). All cellular processes are shaped by the microenvironment and one important factor is the local oxygen tension. The majority of published studies on IFN signalling are conducted under atmospheric (18%) oxygen conditions, that do not reflect the physiological oxygen levels in most organs (1-5% O2). We studied the effect of low oxygen on IFN induction and signalling in induced Pluripotent Stem Cell (iPSC)-derived macrophages as a model for tissue-resident macrophages and assessed the consequence for Zika virus (ZIKV) replication. Hypoxic conditions dampened the expression of interferon-stimulated genes (ISGs) following RLR stimulation or IFN treatment at early time points. RNA-sequencing and bio-informatic analysis uncovered several pathways including changes in transcription factor availability, the presence of HIF binding sites in promoter regions, and CpG content that may contribute to the reduced ISG expression. Importantly, hypoxic conditions increased ZIKV replication at early time points, emphasizing the importance of understanding how low oxygen conditions in the local microenvironment affect pathogen sensing and host defence.

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Section: Discussionmentioning

confidence: 99%

Hypoxia dampens innate immune signalling at early time points and increases Zika virus replication in iPSC-derived macrophages

Schilling

Vaughan-Jackson

James

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Miar and colleagues reported a minimal role for HIF-1α or HIF-2α in regulating the hypoxic suppression of ISGs in cancer cell lines, but decreased chromatin accessibility of genomic regions relevant for type I IFN pathways [13]. Recent studies reported that lactate, a glycolytic product that is increased during hypoxia, regulates gene transcription via lactylation of histones [53,54]. In tumor-infiltrating myeloid cells H3K18 lactylation increased N6-adenosine-methyltransferase 70 kDa subunit (Mettl3) expression that modified Jak1 mRNA, thereby strengthening the immunosuppressive functions [55].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia dampens innate immune signalling at early time points and increases Zika virus RNA levels in iPSC-derived macrophages

Schilling

Vaughan-Jackson

James

et al. 2023

Journal of General Virology

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Type I interferons (IFNs) are the major host defence against viral infection and are induced following activation of cell surface or intracellular pattern recognition receptors, including retinoic-acid-inducible gene I (RIG-I)-like receptors (RLRs). All cellular processes are shaped by the microenvironment and one important factor is the local oxygen tension. The majority of published studies on IFN signalling are conducted under laboratory conditions of 18% oxygen (O2), that do not reflect the oxygen levels in most organs (1–5 % O2). We studied the effect of low oxygen on IFN induction and signalling in induced Pluripotent Stem Cell (iPSC)-derived macrophages as a model for tissue-resident macrophages and assessed the consequence for Zika virus (ZIKV) infection. Hypoxic conditions dampened the expression of interferon-stimulated genes (ISGs) following RLR stimulation or IFN treatment at early time points. RNA-sequencing and bio-informatic analysis uncovered several pathways including changes in transcription factor availability, the presence of HIF binding sites in promoter regions, and CpG content that may contribute to the reduced ISG expression. Hypoxic conditions increased the abundance of ZIKV RNA highlighting the importance of understanding how low oxygen conditions in the local microenvironment affect pathogen sensing and host defences.

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“…We have linked PD-L1 regulation of type I IFN to lactate produced during Warburg metabolism. Lactate is no longer considered simply a waste product, and is now known to be involved in the regulation of key oncogenes and tumor suppressor genes ( 58 ) as well as inflammation ( 59 ), and a novel post-translational modification (lactylation) involving addition of lactate to lysine and phenylalanine residues has been shown ( 60, 61 ).…”

Section: Discussionmentioning

confidence: 99%

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway

Hodgins

Abou-Hamad

Hagerman

et al. 2022

Preprint

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Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced infection with oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 suppressed type I interferon by promoting a metabolic shift characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD-L1-expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.Once sentence summaryPD-L1 promotes oncolytic virus efficacy.

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Lactylation: a Passing Fad or the Future of Posttranslational Modification

Cited by 41 publications

References 78 publications

Hypoxia dampens innate immune signalling at early time points and increases Zika virus replication in iPSC-derived macrophages

Hypoxia dampens innate immune signalling at early time points and increases Zika virus replication in iPSC-derived macrophages

Hypoxia dampens innate immune signalling at early time points and increases Zika virus RNA levels in iPSC-derived macrophages

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway

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