title: Dengue viral protease interaction with NF-κB inhibitor α/β results in endothelial cell apoptosis and hemorrhage development.
abstract: Hemorrhagic manifestations occur frequently accompanying a wide range of dengue disease syndromes. Much work has focused on the contribution of immune factors to the pathogenesis of hemorrhage, but how dengue virus (DENV) participates in the pathogenic process has never been explored. Although there is no consensus that apoptosis is the basis of vascular permeability in human dengue infections, we showed in dengue hemorrhage mouse model that endothelial cell apoptosis is important to hemorrhage development in mice. To explore the molecular basis of the contribution of DENV to endothelial cell death, we show in this study that DENV protease interacts with cellular IκBα and IκBβ and cleaves them. By inducing IκBα and IκBβ cleavage and IκB kinase activation, DENV protease activates NF-κB, which results in endothelial cell death. Intradermal inoculation of DENV protease packaged in adenovirus-associated virus-9 induces endothelial cell death and dermal hemorrhage in mice. Although the H51 activity site is not involved in the interaction between DENV protease and IκB-α/β, the enzymatic activity is critical to the ability of DENV protease to induce IκBα and IκBβ cleavage and trigger hemorrhage development. Moreover, overexpression of IκBα or IκBβ protects endothelial cells from DENV-induced apoptosis. In this study, we show that DENV protease participates in the pathogenesis of dengue hemorrhage and discover IκBα and IκBβ to be the new cellular targets that are cleaved by DENV protease.
authors: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan;
authors: Jung-Chen
authors: JC
authors: Lin
authors: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan;
authors: Shih-Ching
authors: SC
authors: Lin
authors: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan;
authors: Wen-Yu
authors: WY
authors: Chen
authors: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan;
authors: Yu-Ting
authors: YT
authors: Yen
authors: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; and Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors: Chin-Wen
authors: CW
authors: Lai
authors: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; and Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors: Mi-Hua
authors: MH
authors: Tao
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors: Yi-Ling
authors: YL
authors: Lin
authors: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan;
authors: Shi-Chuen
authors: SC
authors: Miaw
authors: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan; bwh@ntu.edu.tw.
authors: Betty A
authors: BA
authors: Wu-Hsieh
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism / Q000502:physiology; D017209:Apoptosis / Q000276:immunology*; D002199:Capillary Permeability / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D003715:Dengue / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology / Q000821:virology; D057809:HEK293 Cells; D006470:Hemorrhage / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000502:physiology; D000085242:Viral Proteases
chemical_list: D000956:Antigens, Viral; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D012697:Serine Endopeptidases; C083487:I kappa B beta protein; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases