Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
Igor Jurak
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Eui Tae Kim
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Ju Youn Kim
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
Michael Hackenberg
Department of Genetics, Computational Genomics and Bioinformatics Group, University of Granada, Granada 18071, Spain
Andrew Leader
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Michelle L. Stoller
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Donna M. Fekete
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Matthew D. Weitzman
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Donald M. Coen
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Angus C. Wilson
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of short non-coding RNAs that regulate mRNA stability/translation, remains largely unexplored. Here we show that transcription of the miR-183 cluster (miR-183, miR-96, and miR-182) is selectively induced by HSV-1 during productive infection of primary fibroblasts and neurons. ICP0, a viral E3 ubiquitin ligase expressed as an immediate-early protein, is both necessary and sufficient for this induction. Nuclear exclusion of ICP0 or removal of the RING (really interesting new gene) finger domain that is required for E3 ligase activity prevents induction. ICP0 promotes the degradation of numerous host proteins and for the most part, the downstream consequences are unknown. Induction of the miR-183 cluster can be mimicked by depletion of host transcriptional repressors zinc finger E-box binding homeobox 1 (ZEB1)/-crystallin enhancer binding factor 1 (δEF1) and zinc finger E-box binding homeobox 2 (ZEB2)/Smad-interacting protein 1 (SIP1), which we establish as new substrates for ICP0-mediated degradation. Thus, HSV-1 selectively stimulates expression of the miR-183 cluster by ICP0-mediated degradation of ZEB transcriptional repressors.
