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

Shuai Wang; Feng Xie; Feng Chu; Zhengkui Zhang; Bing Yang; Tong Dai; Liang Gao; Lin Wang; Li Ling; Junling Jia; Hans van Dam; Jin Jin; Long Zhang; Fangfang Zhou

doi:10.1038/ni.3744

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

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

Authors

Shuai Wang¹, Feng Xie², Feng Chu¹, Zhengkui Zhang², Bing Yang³, Tong Dai¹, Liang Gao¹, Lin Wang¹, Li Ling¹, Junling Jia², Hans van Dam⁴, Jin Jin², Long Zhang², Fangfang Zhou¹

Affiliations

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.

PMID: 28481329
DOI: 10.1038/ni.3744

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / immunology*
Adaptor Proteins, Signal Transducing / metabolism
Animals
CRISPR-Cas Systems
Cell Cycle Proteins
Chemokine CCL5 / genetics
Chemokine CCL5 / immunology
Chemokine CXCL10 / genetics
Chemokine CXCL10 / immunology
Fibroblasts / immunology*
Fluorescent Antibody Technique
Gene Editing
HEK293 Cells
HeLa Cells
Humans
I-kappa B Kinase / metabolism*
Immunity, Innate / immunology*
Immunoblotting
Immunoprecipitation
Interferon Regulatory Factor-3 / genetics
Interferon Regulatory Factor-3 / immunology
Interferon Regulatory Factor-3 / metabolism
Interferon-beta / genetics
Interferon-beta / immunology
Lung / immunology
Lung / pathology
Lysosomes / metabolism*
Macrophages / immunology*
Mice
Microscopy, Confocal
Phosphoproteins / genetics
Phosphoproteins / immunology*
Phosphoproteins / metabolism
Phosphorylation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / immunology
RAW 264.7 Cells
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Rhabdoviridae Infections / immunology*
Rhabdoviridae Infections / pathology
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / immunology
Vesiculovirus
Viral Load
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Chemokine CCL5
Chemokine CXCL10
IRF3 protein, human
Interferon Regulatory Factor-3
Irf3 protein, mouse
Phosphoproteins
Tumor Suppressor Proteins
YAP-Signaling Proteins
Yap1 protein, mouse
Interferon-beta
LATS1 protein, human
LATS2 protein, human
Protein Serine-Threonine Kinases
I-kappa B Kinase