Phosphorylation of MAVS/VISA by Nemo-like kinase (NLK) for degradation regulates the antiviral innate immune response
Authors: Hui-Hui Zhang
Xi-Chen Huang
Yi Liu
Tian-Zi Liuyu
Bo Zhong
Shang-Ze Li
Wei Song
Qi-Peng Shu
Xiao-Dong Zhang
Run-Lei Du
Chao Li
Bing-Xue Jin
Yang Song
Journal: Nature Communications (2019)
Discipline: Multidisciplinary
Keywords: MAVS; NLK; antiviral immunity; degradation; cytokine production
Affiliations: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China. ., Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. ., Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China., College of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China., College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China., Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100005, China. ., College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China. .

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. 

Retracted: No

PubPeer comments:
 They claim that NLK only targets MAVS accroding to the DLR assay result. ![file] , 
 IF data showed that Sev infection increase the expression of MAVS in WT group, but Wb showed that it decrease MAVS expression. ![file] , 
 It s happy that our paper have your attentionuff01 #1 We have discussed this point. And I listed below  We have previously shown that NLK plays an important role in TNFu03b1-induced NF-u03baB signaling. We elucidated the contribution of NLK to the IRF3 and NF-u03baB pathways, in which the kinase activity of NLK is required for IRF3 signaling but is not necessary for the NF-u03baB pathway. NAMDAP plays a notable rescue role in antiviral response inhibition by NLK but a relatively weak role in promoting the virus-induced antiviral response, revealing another potent target of NLK in the innate immune response. Further- more, NLK has been reported to suppress the expression of a wide range of genes through the CREB binding protein (CBP) coactivator47. Thus, NLK potentially controls the innate immunity-related transcription factor complex to negatively regulate type I interferon signaling.  #2 For this point, It is well known that Virus infection can promote the oligomerization of MAVS into a large prion-like signaling structure and induce the degradation of MAVS. Our IF analysis obviously shows the aggregation of MAVS after virus infection, but not the increasable expression of MAVS. So these two results arenu2019t actually in conflict. Thanks for your questions and time! ,