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The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons

Daniels, Brian P. ; Kofman, Sigal B. ; Smith, Julian R. ; Norris, Geoffrey T. ; Snyder, Annelise G. ; Kolb, Joseph P. ; Gao, Xia ; Locasale, Jason W. ; Martinez, Jennifer ; Gale, Michael ; Loo, Yueh-Ming ; Oberst, Andrew

Immunity (Cambridge, Mass.), 2019-01, Vol.50 (1), p.64-76.e4 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons
Autor: Daniels, Brian P. ; Kofman, Sigal B. ; Smith, Julian R. ; Norris, Geoffrey T. ; Snyder, Annelise G. ; Kolb, Joseph P. ; Gao, Xia ; Locasale, Jason W. ; Martinez, Jennifer ; Gale, Michael ; Loo, Yueh-Ming ; Oberst, Andrew
Assuntos: Animal models ; Animals ; Antiviral drugs ; Apoptosis ; Bacterial infections ; Cell activation ; Cell Death ; Cell survival ; Cells, Cultured ; Cellular manufacture ; Central nervous system ; Disease Models, Animal ; Enzymes ; Experiments ; Gene expression ; Genomes ; Glycoproteins - genetics ; Glycoproteins - metabolism ; Humans ; Hydro-Lyases - genetics ; Hydro-Lyases - metabolism ; Infections ; Invasiveness ; Kinases ; Metabolism ; Metabolites ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons ; Neurons - physiology ; Neuroprotection ; Pathogenesis ; Principal components analysis ; Proteins ; Receptor-Interacting Protein Serine-Threonine Kinases - genetics ; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism ; Receptors, Pattern Recognition - metabolism ; Replication ; RNA, Viral - immunology ; RNA-Binding Proteins ; Scholarships & fellowships ; Signal transduction ; Signaling ; Software ; Succinate dehydrogenase ; Succinate Dehydrogenase - metabolism ; Succinates - metabolism ; Vector-borne diseases ; Viral infections ; Virus Replication ; Viruses ; West Nile virus ; Zika Virus - physiology ; Zika Virus Infection - immunology
É parte de: Immunity (Cambridge, Mass.), 2019-01, Vol.50 (1), p.64-76.e4
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SourceType-Scholarly Journals-1
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Conceptualization: BPD, YML, AO. Methodology: BPD, JWL, YML, AO. Analysis: BPD, SBK, JRS, GTN, AGS, JPK, XG. Investigation: BPD, SBK, JRS, GTN, AGS, JPK, XG. Resources: JWL, JM, MG. Writing- Original Draft: BPD and AO. Writing- Review and Editing: All authors. Supervision and Funding Acquisition: JWL, JM, MG, YML, AO.
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Descrição: As long-lived post-mitotic cells, neurons employ unique strategies to resist pathogen infection while preserving cellular function. Here, using a murine model of Zika virus (ZIKV) infection, we identified an innate immune pathway that restricts ZIKV replication in neurons and is required for survival upon ZIKV infection of the central nervous system (CNS). We found that neuronal ZIKV infection activated the nucleotide sensor ZBP1 and the kinases RIPK1 and RIPK3, core components of virus-induced necroptotic cell death signaling. However, activation of this pathway in ZIKV-infected neurons did not induce cell death. Rather, RIPK signaling restricted viral replication by altering cellular metabolism via upregulation of the enzyme IRG1 and production of the metabolite itaconate. Itaconate inhibited the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes. These findings demonstrate an immunometabolic mechanism of viral restriction during neuroinvasive infection. [Display omitted] •Components of the necroptotic cell death pathway limit neuronal Zika virus infection•Viral control is due to cell-intrinsic limitation of viral growth, not cell death•Upregulation of the metabolic enzyme IRG1 in neurons underlies viral restriction•Itaconate, the product of IRG1, induces an antiviral metabolic state in neurons Daniels et al. find that molecules traditionally associated with necroptotic cell death engage a death-independent transcriptional program in neurons during Zika virus infection. This transcriptional program includes the enzyme IRG1, whose product, itaconate, reprograms neuronal metabolism in a manner that restricts Zika virus replication.
Editor: United States: Elsevier Inc
Idioma: Inglês

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The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons

Daniels, Brian P. ; Kofman, Sigal B. ; Smith, Julian R. ; Norris, Geoffrey T. ; Snyder, Annelise G. ; Kolb, Joseph P. ; Gao, Xia ; Locasale, Jason W. ; Martinez, Jennifer ; Gale, Michael ; Loo, Yueh-Ming ; Oberst, Andrew

United States: Elsevier Inc

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