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• W3157264842 abstract "Cellular metabolism and immune function are closely linked. In this issue of Cell Metabolism, Shen et al., 2021Shen L. Hu P. Zhang Y. Ji Z. Shan X. Ni L. Ning N. Wang J. Tian H. Shui G. et al.Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation.Cell Metab. 2021; 33 (this issue): 971-987Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar identify serine metabolism as a central integration hub of cellular metabolism, antiviral immunity, and epigenetic regulation. Cellular metabolism and immune function are closely linked. In this issue of Cell Metabolism, Shen et al., 2021Shen L. Hu P. Zhang Y. Ji Z. Shan X. Ni L. Ning N. Wang J. Tian H. Shui G. et al.Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation.Cell Metab. 2021; 33 (this issue): 971-987Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar identify serine metabolism as a central integration hub of cellular metabolism, antiviral immunity, and epigenetic regulation. Innate immunity evolved to readily detect and rapidly counteract replication of a broad range of pathogens. Specialized pattern recognition receptors (PRRs) recognize pathogens via distinct features, such as nucleic acids. PRR activation by viruses initiates downstream signaling cascades culminating in TBK1 activation and subsequent phosphorylation, dimerization, and nuclear localization of IRF3 to induce expression of type I interferon (IFN-I, including IFN-α and IFN-β). IFN-I signals in a paracrine and autocrine fashion to combat viral pathogens by inducing the expression of hundreds of antiviral IFN-stimulated genes (ISGs) (Schoggins et al., 2011Schoggins J.W. Wilson S.J. Panis M. Murphy M.Y. Jones C.T. Bieniasz P. Rice C.M. A diverse range of gene products are effectors of the type I interferon antiviral response.Nature. 2011; 472: 481-485Crossref PubMed Scopus (1530) Google Scholar). IFN-I also reprograms metabolic pathways as yet another regulatory mechanism of antiviral immune responses (Fritsch and Weichhart, 2016Fritsch S.D. Weichhart T. Effects of interferons and viruses on metabolism.Front. Immunol. 2016; 7: 630Crossref PubMed Scopus (54) Google Scholar; Lercher et al., 2019Lercher A. Bhattacharya A. Popa A.M. Caldera M. Schlapansky M.F. Baazim H. Agerer B. Gürtl B. Kosack L. Májek P. et al.Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function.Immunity. 2019; 51: 1074-1087.e9Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Research in cellular and systemic immunometabolism has provided crucial insights into the crosstalk between innate immune signaling and metabolic pathways that acts to counter pathogens and support inter-organ communication during disease (Lercher et al., 2020Lercher A. Baazim H. Bergthaler A. Systemic immunometabolism: challenges and opportunities.Immunity. 2020; 53: 496-509Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). As such, extracellular availability and metabolism of amino acids represents a central regulatory node for immune responses and pathology in infectious and autoimmune diseases (Ma et al., 2017Ma E.H. Bantug G. Griss T. Condotta S. Johnson R.M. Samborska B. Mainolfi N. Suri V. Guak H. Balmer M.L. et al.Serine is an essential metabolite for effector T cell expansion.Cell Metab. 2017; 25: 345-357Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar; Murray, 2016Murray P.J. Amino acid auxotrophy as a system of immunological control nodes.Nat. Immunol. 2016; 17: 132-139Crossref PubMed Scopus (122) Google Scholar; Roy et al., 2020Roy D.G. Chen J. Mamane V. Ma E.H. Muhire B.M. Sheldon R.D. Shorstova T. Koning R. Johnson R.M. Esaulova E. et al.Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming.Cell Metab. 2020; 31: 250-266.e9Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Immune-mediated reprogramming of methionine and serine metabolism is particularly intriguing, as those pathways directly fuel S-adenosyl-methionine (SAM) production—the substrate for histone methylation. Hence, reprogramming of this metabolic node may influence the epigenome and gene expression (Intlekofer and Finley, 2019Intlekofer A.M. Finley L.W.S. Metabolic signatures of cancer cells and stem cells.Nat Metab. 2019; 1: 177-188Crossref PubMed Scopus (106) Google Scholar; Roy et al., 2020Roy D.G. Chen J. Mamane V. Ma E.H. Muhire B.M. Sheldon R.D. Shorstova T. Koning R. Johnson R.M. Esaulova E. et al.Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming.Cell Metab. 2020; 31: 250-266.e9Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar), which is likely to contribute to the formation of immunological memory and trained immunity. Consistent with previous studies, new work from Shen et al. demonstrates that viral pattern recognition and IFN-I signaling repress cellular amino acid metabolism (Lercher et al., 2019Lercher A. Bhattacharya A. Popa A.M. Caldera M. Schlapansky M.F. Baazim H. Agerer B. Gürtl B. Kosack L. Májek P. et al.Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function.Immunity. 2019; 51: 1074-1087.e9Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar; Shen et al., 2021Shen L. Hu P. Zhang Y. Ji Z. Shan X. Ni L. Ning N. Wang J. Tian H. Shui G. et al.Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation.Cell Metab. 2021; 33 (this issue): 971-987Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). Their study, in this issue of Cell Metabolism, tackles the question of how serine metabolism impacts cellular antiviral immunity and the pathophysiology of viral infections on an organismal level (Figure 1). Mechanistically, viral infection and IFN-I repress the serine-synthesis pathway (SSP) in macrophages. Through a combination of a conditional mouse model and elegant biochemical assays, the authors show that virus-induced repression of the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH) is critical for adequate activation of the TBK1-IRF3 pathway and subsequent IFN-I production. Consistently, this was accompanied by reduced viral loads in PHGDH-deficient cells. Shen and colleagues went on to elucidate that extracellular serine restriction boosted IFN-I production in wild-type macrophages. Interestingly, serine supplementation counteracted the increased IFN-I expression of PHGDH-deficient macrophages, which suggests that excess extracellular serine can dampen the IFN-I response independent of PHGDH. These findings were corroborated with an in vivo infection model using vesicular stomatitis virus, whereby macrophage-specific ablation of PHGDH was associated with reduced viral loads and lethality, correlating with increased IFN-I activity. Both pharmacological inhibition of PHGDH and feeding mice a serine/glycine-deficient diet phenocopied these observations, providing complementary evidence that serine metabolism suppresses IFN-I responses. To delineate which downstream processes are involved in the suppression of IFN-I signaling by serine metabolism, the authors tested the potential of downstream metabolites to counteract increased IFN-I production of serine/glycine-starved macrophages. Strikingly, only supplementation of SAM, an essential metabolite required for the deposition of histone methylation marks and epigenetic regulation of gene expression (Intlekofer and Finley, 2019Intlekofer A.M. Finley L.W.S. Metabolic signatures of cancer cells and stem cells.Nat Metab. 2019; 1: 177-188Crossref PubMed Scopus (106) Google Scholar; Roy et al., 2020Roy D.G. Chen J. Mamane V. Ma E.H. Muhire B.M. Sheldon R.D. Shorstova T. Koning R. Johnson R.M. Esaulova E. et al.Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming.Cell Metab. 2020; 31: 250-266.e9Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar), reverted the increased IFN-I production. Complementary, infection-associated reduction of serine metabolism correlated with decreased H3K27me3 histone marks, which was rescued by supplementation of SAM. RNA sequencing identified a strong enrichment of lysosome-associated genes differentially expressed in PHGDH-deficient compared to wild-type macrophages. Among these genes, the authors focused on the lysosome-related gene V-ATPase subunit ATP6V0d2. Overexpression of ATP6V0d2 phenocopied PHGDH deficiency and increased IFN-I levels upon viral infection. PHGDH-deficient cells showed decreased deposition of the repressive H3K27me3 histone mark at the promoter of ATP6V0d2, suggesting that serine metabolism reduces expression of ATP6V0d2 via chromatin modifications. Contrary to macrophage-specific PHGDH knockout, mice deficient in ATP6V0d2 displayed decreased IFN-I levels and increased viremia. Complemented by in vitro experiments, this indicates that ATP6V0d2 indeed mediates efficient IFN-I responses via the TBK1-IRF3 axis upon infection. Finally, the authors provide evidence that ATP6V0d2-mediated lysosomal degradation of the TBK1-IRF3 inhibitor YAP licenses adequate antiviral innate immune response, including IFN-I production. Taken together, Shen et al. show that virus-induced inhibition of serine metabolism reduces repressive histone methylation to induce ATP6V0d2 expression. This promotes lysosomal degradation of YAP to facilitate TBK1-IRF3 signaling and boost IFN-I expression. This novel “metabo-epi-immune” regulatory mechanism expands our knowledge of how infection-induced metabolic reprogramming shapes the epigenome and gene regulation to combat viral pathogens. Future studies may address whether this IFN-I-mediated decrease of serine metabolism in macrophages frees up serine for utilization by T cells (Lercher et al., 2020Lercher A. Baazim H. Bergthaler A. Systemic immunometabolism: challenges and opportunities.Immunity. 2020; 53: 496-509Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar; Ma et al., 2017Ma E.H. Bantug G. Griss T. Condotta S. Johnson R.M. Samborska B. Mainolfi N. Suri V. Guak H. Balmer M.L. et al.Serine is an essential metabolite for effector T cell expansion.Cell Metab. 2017; 25: 345-357Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar; Murray, 2016Murray P.J. Amino acid auxotrophy as a system of immunological control nodes.Nat. Immunol. 2016; 17: 132-139Crossref PubMed Scopus (122) Google Scholar). It is also tempting to speculate that increased IFN-I signaling might be yet another mechanism of how serine deprivation enhances cancer therapy (Kanarek et al., 2020Kanarek N. Petrova B. Sabatini D.M. Dietary modifications for enhanced cancer therapy.Nature. 2020; 579: 507-517Crossref PubMed Scopus (76) Google Scholar). The demonstrated reduction of H3K27me3 mediated by infection-induced repression of serine metabolism represents a powerful regulatory mechanism that impacts additional aspects of immune regulation, providing yet another intriguing facet to our expanding knowledge at the frontiers of metabolism, epigenetics, and immunity. The authors declare no competing interests. Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradationShen et al.Cell MetabolismApril 1, 2021In BriefHost cells co-regulate their metabolism with innate immune activation to counter virus infection. Shen et al. reveal a critical role for serine metabolism in blocking antiviral innate immunity and show that serine metabolism deficiency reduces SAM-mediated H3K27me3 and promotes ATP6V0d2 expression to enhance YAP lysosomal degradation and virus-induced IFN-β production. Full-Text PDF" @default.
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• W3157264842 title "The serine’s call: Suppressing interferon responses" @default.
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