Abstract
The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defence. The correlation between cellular nutrient/physical status and host antiviral defence is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through the transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 Lys63-linked ubiquitylation and the binding of adaptors/substrates. Accordingly, YAP/TAZ deletion/depletion or cellular conditions inactivating YAP/TAZ through Lats1/2 kinases relieve TBK1 suppression and boost antiviral responses, whereas expression of the transcriptionally inactive YAP dampens cytosolic RNA/DNA sensing and weakens the antiviral defence in cells and zebrafish. Thus, we describe a function of YAP/TAZ and the Hippo pathway in innate immunity, by linking cellular nutrient/physical status to antiviral host defence.
MeSH terms
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Acyltransferases
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antiviral Agents / pharmacology
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Cytosol / metabolism*
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DNA / metabolism
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Doxorubicin / pharmacology
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Fluorescent Antibody Technique
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Gene Expression Regulation / drug effects
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HEK293 Cells
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Hippo Signaling Pathway
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Humans
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / metabolism
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Lysine / metabolism
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Mice, Inbred C57BL
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Nucleic Acids / metabolism*
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Phosphoproteins / chemistry
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Phosphoproteins / metabolism*
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Protein Binding / drug effects
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Protein Domains
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Protein Serine-Threonine Kinases / metabolism*
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RNA / metabolism
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Signal Transduction*
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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Transcriptional Activation / genetics
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Tumor Suppressor Proteins / metabolism
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Ubiquitination / drug effects
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YAP-Signaling Proteins
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Zebrafish / embryology
Substances
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Adaptor Proteins, Signal Transducing
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Antiviral Agents
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Nucleic Acids
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Phosphoproteins
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Transcription Factors
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Tumor Suppressor Proteins
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YAP-Signaling Proteins
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YAP1 protein, human
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RNA
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Doxorubicin
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DNA
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Acyltransferases
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TAFAZZIN protein, human
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LATS1 protein, human
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LATS2 protein, human
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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Lysine