dengue virus capsid protein binds core histones and inhibits nucleosome formation in human liver cells登革病毒衣壳蛋白结合核心在人类肝细胞组蛋白和抑制核小体的形成.pdfVIP

Dengue Virus Capsid Protein Binds Core Histones and Inhibits Nucleosome Formation in Human Liver Cells 1 3 1 1,2 Tonya M. Colpitts , Sebastian Barthel , Penghua Wang , Erol Fikrig * 1 Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America, 2 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America, 3 Interfaculty Institute of Biochemistry, University of Tuebingen, Germany Abstract Dengue virus (DENV) is a member of the Flaviviridae and a globally (re)emerging pathogen that causes serious human disease. There is no specific antiviral or vaccine for dengue virus infection. Flavivirus capsid (C) is a structural protein responsible for gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle. Flaviviral replication is known to occur in the cytoplasm yet a large portion of capsid protein localizes to the nucleus during infection. The reasons for the nuclear presences of capsid are not completely understood. Here, we expressed mature DENV C in a tandem affinity purification assay to identify potential binding partners in human liver cells. DENV C targeted the four core histones, H2A, H2B, H3 and H4. DENV C bound recombinant histones in solution and colocalized with histones in the nucleus and cytoplasm of liver cells during DENV infection. We show that DENV C acts as a histone mimic, forming heterodimers with core histones, binding DNA and disrupting nucleosome formation. We also demonstrate that DENV infection increases the amounts of