한빛사 논문
제주대학교 의과대학, University of Pennsylvania & Children's Hospital of Philadelphia
Eui Tae Kim1,2,3, Joseph M. Dybas1,2,4, Katarzyna Kulej1,5, Emigdio D. Reyes1,2, Alexander M. Price1,2, Lisa N. Akhtar1,6, Ann Orr7, Benjamin A. Garcia5,8, Chris Boutell7 and Matthew D. Weitzman1,2,8,*
1Division of Protective Immunity and Division of Cancer Pathobiology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 2Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 3Department of Microbiology and Immunology, Jeju National University School of Medicine, Jeju, Republic of Korea. 4Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 5Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 6Division of Infectious Diseases, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 7MRC-University of Glasgow Center for Virus Research, Glasgow, UK. 8Epigenetics Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
*Corresponding author
Abstract
Intrinsic antiviral host factors confer cellular defence by limiting virus replication and are often counteracted by viral countermeasures. We reasoned that host factors that inhibit viral gene expression could be identified by determining proteins bound to viral DNA (vDNA) in the absence of key viral antagonists. Herpes simplex virus 1 (HSV-1) expresses E3 ubiquitin-protein ligase ICP0 (ICP0), which functions as an E3 ubiquitin ligase required to promote infection. Cellular substrates of ICP0 have been discovered as host barriers to infection but the mechanisms for inhibition of viral gene expression are not fully understood. To identify restriction factors antagonized by ICP0, we compared proteomes associated with vDNA during HSV-1 infection with wild-type virus and a mutant lacking functional ICP0 (ΔICP0). We identified the cellular protein Schlafen family member 5 (SLFN5) as an ICP0 target that binds vDNA during HSV-1 ΔICP0 infection. We demonstrated that ICP0 mediates ubiquitination of SLFN5, which leads to its proteasomal degradation. In the absence of ICP0, SLFN5 binds vDNA to repress HSV-1 transcription by limiting accessibility of RNA polymerase II to viral promoters. These results highlight how comparative proteomics of proteins associated with viral genomes can identify host restriction factors and reveal that viral countermeasures can overcome SLFN antiviral activity.
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