title: Dengue virus subverts the interferon induction pathway via NS2B/3 protease-IκB kinase epsilon interaction.
abstract: Dengue is the world's most common mosquito-borne viral infection and a leading cause of morbidity throughout the tropics and subtropics. Viruses are known to evade the establishment of an antiviral state by regulating the activation of interferon regulatory factor 3 (IRF3), a critical transcription factor in the alpha/beta interferon induction pathway. Here, we show that dengue virus (DENV) circumvents the induction of the retinoic acid-inducible gene I-like receptor (RLR) pathway during infection by blocking serine 386 phosphorylation and nuclear translocation of IRF3. This effect is associated with the expression of nonstructural 2B/3 protein (NS2B/3) protease in human cells. Using interaction assays, we found that NS2B/3 interacts with the cellular IκB kinase ε (IKKε). Docking computational analysis revealed that in this interaction, NS2B/3 masks the kinase domain of IKKε and potentially affects its functionality. This observation is supported by the DENV-associated inhibition of the kinase activity of IKKε. Our data identify IKKε as a novel target of DENV NS2B/3 protease.
authors.affiliation: Department of Microbiology and Medical Zoology, University of Puerto Rico, Medical Science Campus, San Juan, Puerto Rico.
authors.forename: Yesseinia I
authors.initials: YI
authors.lastname: Angleró-Rodríguez
authors.forename: Petraleigh
authors.initials: P
authors.lastname: Pantoja
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Sariol
mesh_terms: D002478:Cells, Cultured; D003716:Dengue Virus / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057131:Immune Evasion; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D062105:Molecular Docking Simulation; D025941:Protein Interaction Mapping; D012697:Serine Endopeptidases / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D000085242:Viral Proteases
chemical_list: D051550:I-kappa B Kinase; D007372:Interferons; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases