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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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
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Abstract	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.
AbstractList	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 ) 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. 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+NDR2f/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. 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. 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+NDR2f/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.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+NDR2f/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.
Author	Liu, Zhiyong Pan, Yueyun Zhang, Yuanyuan Liu, Huan Wang, Xiumei Wang, Xiaojian Gu, Meidi Yang, Yuting Wu, Cheng
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Snippet	NDR2 functions as an antiviral molecule via regulating TRIM25-mediated RIG-I activation. Retinoic acid–inducible gene I (RIG-I), a pivotal cytosolic sensor,... Retinoic acid-inducible gene I (RIG-I), a pivotal cytosolic sensor, recognizes viral RNAs to initiate antiviral innate immunity. However, posttranslational... NDR2 functions as an antiviral molecule via regulating TRIM25-mediated RIG-I activation. Retinoic acid–inducible gene I (RIG-I), a pivotal cytosolic sensor,...
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SubjectTerms	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
Title	NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages
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