Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling
Identifieur interne : 000B95 ( Pmc/Curation ); précédent : 000B94; suivant : 000B96Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling
Auteurs : Fanhua Wei [République populaire de Chine] ; Zhimin Jiang [République populaire de Chine] ; Honglei Sun [République populaire de Chine] ; Juan Pu [République populaire de Chine] ; Yipeng Sun [République populaire de Chine] ; Mingyang Wang [République populaire de Chine] ; Qi Tong [République populaire de Chine] ; Yuhai Bi [République populaire de Chine] ; Xiaojing Ma [République populaire de Chine, États-Unis] ; George Fu Gao [République populaire de Chine] ; Jinhua Liu [République populaire de Chine]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2019.
Abstract
Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both
Url:
DOI: 10.1371/journal.ppat.1008062
PubMed: 31585000
PubMed Central: 6795447
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling</title>
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<author><name sortKey="Gao, George Fu" sort="Gao, George Fu" uniqKey="Gao G" first="George Fu" last="Gao">George Fu Gao</name>
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<author><name sortKey="Liu, Jinhua" sort="Liu, Jinhua" uniqKey="Liu J" first="Jinhua" last="Liu">Jinhua Liu</name>
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<series><title level="j">PLoS Pathogens</title>
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<front><div type="abstract" xml:lang="en"><p>Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both <italic>in vitro</italic>
and <italic>in vivo</italic>
during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity.</p>
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<author><name sortKey="Welteke, V" uniqKey="Welteke V">V Welteke</name>
</author>
<author><name sortKey="Oeckinghaus, A" uniqKey="Oeckinghaus A">A Oeckinghaus</name>
</author>
<author><name sortKey="Baens, M" uniqKey="Baens M">M Baens</name>
</author>
<author><name sortKey="Kloo, B" uniqKey="Kloo B">B Kloo</name>
</author>
<author><name sortKey="Ferch, U" uniqKey="Ferch U">U Ferch</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Martens, Lh" uniqKey="Martens L">LH Martens</name>
</author>
<author><name sortKey="Zhang, J" uniqKey="Zhang J">J Zhang</name>
</author>
<author><name sortKey="Barmada, Sj" uniqKey="Barmada S">SJ Barmada</name>
</author>
<author><name sortKey="Zhou, P" uniqKey="Zhou P">P Zhou</name>
</author>
<author><name sortKey="Kamiya, S" uniqKey="Kamiya S">S Kamiya</name>
</author>
<author><name sortKey="Sun, B" uniqKey="Sun B">B Sun</name>
</author>
</analytic>
</biblStruct>
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</author>
<author><name sortKey="Ohama, T" uniqKey="Ohama T">T Ohama</name>
</author>
<author><name sortKey="Matsuyama, A" uniqKey="Matsuyama A">A Matsuyama</name>
</author>
<author><name sortKey="Matsuwaki, T" uniqKey="Matsuwaki T">T Matsuwaki</name>
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<author><name sortKey="Okada, T" uniqKey="Okada T">T Okada</name>
</author>
<author><name sortKey="Yamashita, T" uniqKey="Yamashita T">T Yamashita</name>
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</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tian, R" uniqKey="Tian R">R Tian</name>
</author>
<author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name>
</author>
<author><name sortKey="Yao, X" uniqKey="Yao X">X Yao</name>
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</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Huang, K" uniqKey="Huang K">K Huang</name>
</author>
<author><name sortKey="Chen, A" uniqKey="Chen A">A Chen</name>
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<author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name>
</author>
<author><name sortKey="Song, Z" uniqKey="Song Z">Z Song</name>
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<biblStruct><analytic><author><name sortKey="Jacques, P" uniqKey="Jacques P">P Jacques</name>
</author>
<author><name sortKey="Elewaut, D" uniqKey="Elewaut D">D Elewaut</name>
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</analytic>
</biblStruct>
</listBibl>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plospath</journal-id>
<journal-title-group><journal-title>PLoS Pathogens</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7366</issn>
<issn pub-type="epub">1553-7374</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31585000</article-id>
<article-id pub-id-type="pmc">6795447</article-id>
<article-id pub-id-type="doi">10.1371/journal.ppat.1008062</article-id>
<article-id pub-id-type="publisher-id">PPATHOGENS-D-18-02446</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>RNA viruses</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical Microbiology</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Pathology and Laboratory Medicine</subject>
<subj-group><subject>Pathogens</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Physiology</subject>
<subj-group><subject>Immune Physiology</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Physiology</subject>
<subj-group><subject>Immune Physiology</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune System Proteins</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune System Proteins</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Immune System Proteins</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Infectious Diseases</subject>
<subj-group><subject>Viral Diseases</subject>
<subj-group><subject>Influenza</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Molecular Biology</subject>
<subj-group><subject>Molecular Biology Techniques</subject>
<subj-group><subject>Transfection</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject>
<subj-group><subject>Molecular Biology Techniques</subject>
<subj-group><subject>Transfection</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Genetics</subject>
<subj-group><subject>Gene expression</subject>
<subj-group><subject>Gene regulation</subject>
<subj-group><subject>Small interfering RNAs</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Nucleic acids</subject>
<subj-group><subject>RNA</subject>
<subj-group><subject>Non-coding RNA</subject>
<subj-group><subject>Small interfering RNAs</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Cell Biology</subject>
<subj-group><subject>Cellular Types</subject>
<subj-group><subject>Animal Cells</subject>
<subj-group><subject>Blood Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>Macrophages</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Cell Biology</subject>
<subj-group><subject>Cellular Types</subject>
<subj-group><subject>Animal Cells</subject>
<subj-group><subject>Immune Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>Macrophages</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>Macrophages</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>Macrophages</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Post-Translational Modification</subject>
<subj-group><subject>Ubiquitination</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>RNA viruses</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
<subj-group><subject>H5N1</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical microbiology</subject>
<subj-group><subject>Microbial pathogens</subject>
<subj-group><subject>Viral pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
<subj-group><subject>H5N1</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and health sciences</subject>
<subj-group><subject>Pathology and laboratory medicine</subject>
<subj-group><subject>Pathogens</subject>
<subj-group><subject>Microbial pathogens</subject>
<subj-group><subject>Viral pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
<subj-group><subject>H5N1</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>Viral pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
<subj-group><subject>H5N1</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Infectious Diseases</subject>
<subj-group><subject>Zoonoses</subject>
<subj-group><subject>H5N1</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling</article-title>
<alt-title alt-title-type="running-head">PGRN deficiency enhances the antiviral immune responses during influenza virus infection</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-2997-922X</contrib-id>
<name><surname>Wei</surname>
<given-names>Fanhua</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Jiang</surname>
<given-names>Zhimin</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sun</surname>
<given-names>Honglei</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pu</surname>
<given-names>Juan</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sun</surname>
<given-names>Yipeng</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Mingyang</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tong</surname>
<given-names>Qi</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bi</surname>
<given-names>Yuhai</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ma</surname>
<given-names>Xiaojing</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-3869-615X</contrib-id>
<name><surname>Gao</surname>
<given-names>George Fu</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Jinhua</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>College of Agriculture, Ningxia University, Yinchuan, China</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Institute of Microbiology, Center for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences, Beijing, China</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China</addr-line>
</aff>
<aff id="aff005"><label>5</label>
<addr-line>Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Heise</surname>
<given-names>Mark T.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of North Carolina at Chapel Hill, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p>
</fn>
<corresp id="cor001">* E-mail: <email>weifanhua999@163.com</email>
(FW); <email>ljh@cau.edu.cn</email>
(JL)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>4</day>
<month>10</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>10</month>
<year>2019</year>
</pub-date>
<volume>15</volume>
<issue>10</issue>
<elocation-id>e1008062</elocation-id>
<history><date date-type="received"><day>21</day>
<month>12</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>2</day>
<month>9</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 Wei et al</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>Wei et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="ppat.1008062.pdf"></self-uri>
<abstract><p>Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both <italic>in vitro</italic>
and <italic>in vivo</italic>
during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity.</p>
</abstract>
<abstract abstract-type="summary"><title>Author summary</title>
<p>The innate immune system is the first line of host defense against microbial infection, while viruses develop several strategies to evade the host defense. It is of great significance to explore the mechanism by which viruses to evade the antiviral host defense. Previous studies have found that progranulin (PGRN) plays an important role in a variety of physiologic and disease processes. Here, we demonstrated that PGRN induced by influenza virus negatively regulated type I IFN production by inhibiting the activation of NF-κB and IRF3 signaling. We further showed that PGRN directly interacted with NEMO via its Grn CDE domains and recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO. Macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our findings highlight a new strategy whereby influenza virus to evade type I IFN-mediated antiviral immune response and also provide insights into the functions and crosstalk of PGRN in innate immunity.</p>
</abstract>
<funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001809</institution-id>
<institution>National Natural Science Foundation of China</institution>
</institution-wrap>
</funding-source>
<award-id>31672570</award-id>
<principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-2997-922X</contrib-id>
<name><surname>Wei</surname>
<given-names>Fanhua</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001809</institution-id>
<institution>National Natural Science Foundation of China</institution>
</institution-wrap>
</funding-source>
<award-id>31802176</award-id>
<principal-award-recipient><name><surname>Tong</surname>
<given-names>Qi</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award003"><funding-source><institution>National Key Research and Development Program</institution>
</funding-source>
<award-id>2016YFD0500204</award-id>
<principal-award-recipient><name><surname>Liu</surname>
<given-names>Jinhua</given-names>
</name>
</principal-award-recipient>
</award-group>
<funding-statement>This work was supported by the National Natural Science Foundation of China (NSFC) (31672570, 31802176) and National Key Research and Development Program (2016YFD0500204). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="13"></fig-count>
<table-count count="0"></table-count>
<page-count count="26"></page-count>
</counts>
<custom-meta-group><custom-meta><meta-name>PLOS Publication Stage</meta-name>
<meta-value>vor-update-to-uncorrected-proof</meta-value>
</custom-meta>
<custom-meta><meta-name>Publication Update</meta-name>
<meta-value>2019-10-16</meta-value>
</custom-meta>
<custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the manuscript and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the manuscript and its Supporting Information files.</p>
</notes>
</front>
</pmc>
</record>
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