Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade

Nat Cell Biol. 2017 Apr;19(4):362-374. doi: 10.1038/ncb3496. Epub 2017 Mar 27.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antiviral Agents / pharmacology
  • Cytosol / metabolism*
  • DNA / metabolism
  • Doxorubicin / pharmacology
  • Fluorescent Antibody Technique
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Lysine / metabolism
  • Mice, Inbred C57BL
  • Nucleic Acids / metabolism*
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism*
  • Protein Binding / drug effects
  • Protein Domains
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA / metabolism
  • Signal Transduction*
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • Transcriptional Activation / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitination / drug effects
  • Zebrafish / embryology

Substances

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Nucleic Acids
  • Phosphoproteins
  • TAZ protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YAP1 (Yes-associated) protein, human
  • RNA
  • Doxorubicin
  • DNA
  • LATS1 protein, human
  • LATS2 protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • Lysine