NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages

NDR2 functions as an antiviral molecule via regulating TRIM25-mediated RIG-I activation. Retinoic acid–inducible gene I (RIG-I), a pivotal cytosolic sensor, recognizes viral RNAs to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling is not well understood. W...

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Bibliographic Details
Published in:Science advances Vol. 5; no. 2; p. eaav0163
Main Authors: Liu, Zhiyong, Wu, Cheng, Pan, Yueyun, Liu, Huan, Wang, Xiumei, Yang, Yuting, Gu, Meidi, Zhang, Yuanyuan, Wang, Xiaojian
Format: Journal Article
Language:English
Published: United States American Association for the Advancement of Science 01.02.2019
Subjects:
Animals
Biomarkers
Cytokines
DEAD Box Protein 58 - metabolism
Disease Models, Animal
Enzyme Activation
Host-Pathogen Interactions - immunology
Humans
Immunity
Immunology
Immunomodulation
Macrophages - immunology
Macrophages - metabolism
Macrophages - virology
Mice
Mice, Knockout
Protein Serine-Threonine Kinases - metabolism
Receptors, Immunologic
SciAdv r-articles
Signal Transduction
Transcription Factors - metabolism
Tripartite Motif Proteins - metabolism
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Virus Diseases - immunology
Virus Diseases - metabolism
Virus Diseases - virology
ISSN:2375-2548, 2375-2548
Online Access:Get full text
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Summary:NDR2 functions as an antiviral molecule via regulating TRIM25-mediated RIG-I activation. Retinoic acid–inducible gene I (RIG-I), a pivotal cytosolic sensor, recognizes viral RNAs to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling is not well understood. We report here that nuclear Dbf2-related kinase 2 (NDR2) functions as a crucial positive regulator of the RIG-I–mediated antiviral immune response. Overexpression of NDR2 or its kinase-inactive mutants potentiates RNA virus–induced production of type I interferons and proinflammatory cytokines and dampens viral replication. NDR2 conditional knockout mice (Lysm + NDR2 f/f ) show an impaired antiviral immune response. Mechanistically, NDR2 directly associates with RIG-I and TRIM25, thus facilitating the RIG-I/TRIM25 complex and enhancing the TRIM25-mediated K63-linked polyubiquitination of RIG-I, which is required for the RIG-I–mediated antiviral immune response. Furthermore, NDR2 expression is notably down-regulated in peripheral blood from respiratory syncytial virus–infected patients and in virus-infected macrophages. Collectively, these findings provide insights into the function of NDR2 in antiviral immunity and its related clinical significance.
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ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aav0163