Phosphorylation of MAVS/VISA by Nemo-like kinase (NLK) for degradation regulates the antiviral innate immune response

Shang-Ze Li (), Qi-Peng Shu, Yang Song, Hui-Hui Zhang, Yi Liu, Bing-Xue Jin, Tian-Zi Liuyu, Chao Li, Xi-Chen Huang, Run-Lei Du, Wei Song (), Bo Zhong () and Xiao-Dong Zhang ()
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Shang-Ze Li: Wuhan University
Qi-Peng Shu: Wuhan University
Yang Song: Wuhan University
Hui-Hui Zhang: Hunan Normal University
Yi Liu: Wuhan University
Bing-Xue Jin: Wuhan University
Tian-Zi Liuyu: Wuhan University
Chao Li: Wuhan University
Xi-Chen Huang: Wuhan University
Run-Lei Du: Wuhan University
Wei Song: Peking Union Medical College
Bo Zhong: Wuhan University
Xiao-Dong Zhang: Wuhan University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract MAVS is essential for antiviral immunity, but the molecular mechanisms responsible for its tight regulation remain poorly understood. Here, we show that NLK inhibits the antiviral immune response during viral infection by targeting MAVS for degradation. NLK depletion promotes virus-induced antiviral cytokine production and decreases viral replication, which is potently rescued by the reintroduction of NLK. Moreover, the depletion of NLK promotes antiviral effects and increases the survival times of mice after infection with VSV. NLK interacts with and phosphorylates MAVS at multiple sites on mitochondria or peroxisomes, thereby inducing the degradation of MAVS and subsequent inactivation of IRF3. Most importantly, a peptide derived from MAVS promotes viral-induced IFN-β production and antagonizes viral replication in vitro and in vivo. These findings provide direct insights into the molecular mechanisms by which phosphorylation of MAVS regulates its degradation and influences its activation and identify an important peptide target for propagating antiviral responses.

Date: 2019
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DOI: 10.1038/s41467-019-11258-x

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