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Nat Immunol. 2017 Jul;18(7):733-743. doi: 10.1038/ni.3744. Epub 2017 May 8.

YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKKɛ-mediated phosphorylation.

Author information

1
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China.
2
Life Sciences Institute and Innovation Center for Cell Signaling Network, Hangzhou, Zhejiang, China.
3
Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
4
Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands.

Abstract

The transcription regulator YAP controls organ size by regulating cell growth, proliferation and apoptosis. However, whether YAP has a role in innate antiviral immunity is largely unknown. Here we found that YAP negatively regulated an antiviral immune response. YAP deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in vivo. YAP blocked dimerization of the transcription factor IRF3 and impeded translocation of IRF3 to the nucleus after viral infection. Notably, virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response. These findings not only establish YAP as a modulator of the activation of IRF3 but also identify a previously unknown regulatory mechanism independent of the kinases Hippo and LATS via which YAP is controlled by the innate immune pathway.

PMID:
28481329
DOI:
10.1038/ni.3744
[Indexed for MEDLINE]

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