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1.
Viruses ; 10(12)2018 12 14.
Article in English | MEDLINE | ID: mdl-30558248

ABSTRACT

Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract disease. Retinoic acid-inducible gene-I (RIG-I) serves as an innate immune sensor and triggers antiviral responses upon recognizing viral infections including RSV. Since tripartite motif-containing protein 25 (TRIM25)-mediated K63-polyubiquitination is crucial for RIG-I activation, several viruses target initial RIG-I activation through ubiquitination. RSV NS1 and NS2 have been shown to interfere with RIG-I-mediated antiviral signaling. In this study, we explored the possibility that NS1 suppresses RIG-I-mediated antiviral signaling by targeting TRIM25. Ubiquitination of ectopically expressed RIG-I-2Cards domain was decreased by RSV infection, indicating that RSV possesses ability to inhibit TRIM25-mediated RIG-I ubiquitination. Similarly, ectopic expression of NS1 sufficiently suppressed TRIM25-mediated RIG-I ubiquitination. Furthermore, interaction between NS1 and TRIM25 was detected by a co-immunoprecipitation assay. Further biochemical assays showed that the SPRY domain of TRIM25, which is responsible for interaction with RIG-I, interacted sufficiently with NS1. Suppression of RIG-I ubiquitination by NS1 resulted in decreased interaction between RIG-I and its downstream molecule, MAVS. The suppressive effect of NS1 on RIG-I signaling could be abrogated by overexpression of TRIM25. Collectively, this study suggests that RSV NS1 interacts with TRIM25 and interferes with RIG-I ubiquitination to suppress type-I interferon signaling.


Subject(s)
DEAD Box Protein 58/genetics , Respiratory Syncytial Virus, Human/physiology , Transcription Factors/genetics , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Ubiquitination , Viral Nonstructural Proteins/genetics , A549 Cells , Cell Line , DEAD Box Protein 58/immunology , DEAD Box Protein 58/metabolism , HEK293 Cells , Humans , Immunity, Innate , Polymerase Chain Reaction , Protein Binding , Receptors, Immunologic , Respiratory Syncytial Virus, Human/genetics , Signal Transduction , Transcription Factors/immunology , Transcription Factors/metabolism , Tripartite Motif Proteins/immunology , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/immunology , Ubiquitin-Protein Ligases/metabolism , Viral Nonstructural Proteins/metabolism
2.
Front Immunol ; 9: 2096, 2018.
Article in English | MEDLINE | ID: mdl-30258449

ABSTRACT

Autophagy has been implicated in innate immune responses against various intracellular pathogens. Recent studies have reported that autophagy can be triggered by pathogen recognizing sensors, including Toll-like receptors and cyclic guanosine monophosphate-adenosine monophosphate synthase, to participate in innate immunity. In the present study, we examined whether the RIG-I signaling pathway, which detects viral infections by recognizing viral RNA, triggers the autophagic process. The introduction of polyI:C into the cytoplasm, or Sendai virus infection, significantly induced autophagy in normal cells but not in RIG-I-deficient cells. PolyI:C transfection or Sendai virus infection induced autophagy in the cells lacking type-I interferon signaling. This demonstrated that the effect was not due to interferon signaling. RIG-I-mediated autophagy diminished by the deficiency of mitochondrial antiviral signaling protein (MAVS) or tumor necrosis factor receptor-associated factor (TRAF)6, showing that the RIG-I-MAVS-TRAF6 signaling axis was critical for RIG-I-mediated autophagy. We also found that Beclin-1 was translocated to the mitochondria, and it interacted with TRAF6 upon RIG-I activation. Furthermore, Beclin-1 underwent K63-polyubiquitination upon RIG-I activation, and the ubiquitination decreased in TRAF6-deficient cells. This suggests that the RIG-I-MAVS-TRAF6 axis induced K63-linked polyubiquitination of Beclin-1, which has been implicated in triggering autophagy. As deficient autophagy increases the type-I interferon response, the induction of autophagy by the RIG-I pathway might also contribute to preventing an excessive interferon response as a negative-feedback mechanism.


Subject(s)
Adaptor Proteins, Signal Transducing/immunology , Autophagy/immunology , Beclin-1/immunology , DEAD Box Protein 58/immunology , Signal Transduction/immunology , TNF Receptor-Associated Factor 6/immunology , Virus Diseases/immunology , Animals , Antigen-Presenting Cells/immunology , CD8-Positive T-Lymphocytes/immunology , Humans , Intracellular Signaling Peptides and Proteins , Receptors, Immunologic
3.
Chem Commun (Camb) ; 53(52): 7045-7047, 2017 Jun 27.
Article in English | MEDLINE | ID: mdl-28653701

ABSTRACT

Despite the diverse pharmacological activities of berberine, including anti-cancer and anti-inflammatory effects, the direct proteomic targets of berberine have remained largely unknown. Here, we have identified actin as a direct proteomic target of berberine using an affinity-based chemical probe. In addition, we found that actin assembly was significantly modulated by berberine in vitro at the biochemical level and cellular level.


Subject(s)
Actins/biosynthesis , Berberine/pharmacology , Molecular Probes/pharmacology , Proteomics , Actins/chemistry , Actins/metabolism , Berberine/chemistry , Molecular Probes/chemistry , Molecular Structure
4.
Biochem Biophys Res Commun ; 477(3): 311-6, 2016 08 26.
Article in English | MEDLINE | ID: mdl-27346133

ABSTRACT

Respiratory syncytial virus (RSV) and influenza A virus are leading causes of acute lower respiratory infectious disease. Respiratory diseases caused by RSV and influenza A virus result in serious economic burden and life-threatening disease for immunocompromised people. With the revelation that p38 mitogen-activated protein kinase (MAPK) activity in host cells is crucial for infection and replication of RSV and influenza A virus, inhibition of p38 MAPK activity has been suggested as a potential antiviral therapeutic strategy. However, the low selectivity and high toxicity of the p38 MAPK inhibitors necessitate the development of better inhibitors. Herein, we report the synthesis of a novel p38 MAPK inhibitor, NJK14047, with high kinase selectivity. In this work, it was demonstrated that NJK14047 inhibits RSV- and influenza A-mediated p38 MAPK activation in epithelial cells. Subsequently, NJK14047 treatment resulted in decreased viral replication and viral mRNA synthesis. In addition, secretion of interleukin-6 from infected cells was greatly diminished by NJK14047, suggesting that it can ameliorate immunopathological responses to RSV and influenza A. Collectively, the results suggest that NJK14047 has therapeutic potential to treat respiratory viral infection through the suppression of p38 MAPK activation, which is suggested to be an essential step for respiratory virus infection.


Subject(s)
Antiviral Agents/pharmacology , Influenza A virus/drug effects , Protein Kinase Inhibitors/pharmacology , Respiratory Syncytial Viruses/drug effects , Virus Replication/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cell Line , Enzyme Activation , Influenza A virus/growth & development , Influenza A virus/physiology , Mice , RNA, Viral/antagonists & inhibitors , RNA, Viral/biosynthesis , Respiratory Syncytial Viruses/growth & development , Respiratory Syncytial Viruses/physiology , Viral Plaque Assay , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
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