title: Ribosome Protein L4 is essential for Epstein-Barr Virus Nuclear Antigen 1 function.
abstract: Epstein-Barr Virus (EBV) Nuclear Antigen 1 (EBNA1)-mediated origin of plasmid replication (oriP) DNA episome maintenance is essential for EBV-mediated tumorigenesis. We have now found that EBNA1 binds to Ribosome Protein L4 (RPL4). RPL4 shRNA knockdown decreased EBNA1 activation of an oriP luciferase reporter, EBNA1 DNA binding in lymphoblastoid cell lines, and EBV genome number per lymphoblastoid cell line. EBV infection increased RPL4 expression and redistributed RPL4 to cell nuclei. RPL4 and Nucleolin (NCL) were a scaffold for an EBNA1-induced oriP complex. The RPL4 N terminus cooperated with NCL-K429 to support EBNA1 and oriP-mediated episome binding and maintenance, whereas the NCL C-terminal K380 and K393 induced oriP DNA H3K4me2 modification and promoted EBNA1 activation of oriP-dependent transcription. These observations provide new insights into the mechanisms by which EBV uses NCL and RPL4 to establish persistent B-lymphoblastoid cell infection.
authors: Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
authors: Chih-Lung
authors: CL
authors: Shen
authors: Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
authors: Cheng-Der
authors: CD
authors: Liu
authors: Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Sec. 3, Hualien 97004, Taiwan;
authors: Ren-In
authors: RI
authors: You
authors: Department of Molecular Biology and Human Genetics, Tzu Chi University, Sec. 3, Hualien 97004, Taiwan;
authors: Yung-Hao
authors: YH
authors: Ching
authors: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors: Jun
authors: J
authors: Liang
authors: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors: Liangru
authors: L
authors: Ke
authors: Department of Life Sciences, Tzu Chi University, Sec. 3, Hualien 97004, Taiwan;
authors: Ya-Lin
authors: YL
authors: Chen
authors: Department of Life Sciences, Tzu Chi University, Sec. 3, Hualien 97004, Taiwan;
authors: Hong-Chi
authors: HC
authors: Chen
authors: Department of Life Sciences, Tzu Chi University, Sec. 3, Hualien 97004, Taiwan;
authors: Hao-Jen
authors: HJ
authors: Hsu
authors: Institute of Biochemical Sciences, Tzu Chi University, Sec. 3, Hualien 97004, Taiwan.
authors: Je-Wen
authors: JW
authors: Liou
authors: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115; ekieff@rics.bwh.harvard.edu pengcw@mail.tcu.edu.tw.
authors: Elliott
authors: E
authors: Kieff
authors: Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan; Department of Life Sciences, Tzu Chi University, Sec. 3, Hualien 97004, Taiwan; ekieff@rics.bwh.harvard.edu pengcw@mail.tcu.edu.tw.
authors: Chih-Wen
authors: CW
authors: Peng
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018741:Replication Origin; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000097796:Nucleolin
chemical_list: D004279:DNA, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D000097796:Nucleolin; C056368:ribosomal protein L4; C417029:EBV-encoded nuclear antigen 1
keywords: EBNA1; EBV; NCL; RPL4; oriP