title: PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection.
abstract: Enhancing the response to interferon could offer an immunological advantage to the host. In support of this concept, we used a modified form of the transcription factor STAT1 to achieve hyper-responsiveness to interferon without toxicity and markedly improve antiviral function in transgenic mice and transduced human cells. We found that the improvement depended on expression of a PARP9-DTX3L complex with distinct domains for interaction with STAT1 and for activity as an E3 ubiquitin ligase that acted on host histone H2BJ to promote interferon-stimulated gene expression and on viral 3C proteases to degrade these proteases via the immunoproteasome. Thus, PARP9-DTX3L acted on host and pathogen to achieve a double layer of immunity within a safe reserve in the interferon signaling pathway.
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Dailing
authors.initials: D
authors.lastname: Mao
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Roswit
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jin
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Anand C
authors.identifier: http://orcid.org/0000-0002-6570-8582
authors.initials: AC
authors.lastname: Patel
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Dhara A
authors.initials: DA
authors.lastname: Patel
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Agapov
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Zhepeng
authors.identifier: http://orcid.org/0000-0003-2835-7098
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Rose M
authors.initials: RM
authors.lastname: Tidwell
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Atkinson
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Guangming
authors.initials: G
authors.lastname: Huang
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: McCarthy
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Yu
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Nadezhda E
authors.initials: NE
authors.lastname: Yun
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Paessler
authors.affiliation: Department of Chemistry, Bates College, Lewiston, Maine, USA.
authors.forename: T Glen
authors.initials: TG
authors.lastname: Lawson
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Omattage
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Biochemistry, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Brett
authors.affiliation: Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
mesh_terms: D000086042:3C Viral Proteases; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004686:Encephalomyocarditis virus / Q000502:physiology; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D015151:Immunoblotting; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D012194:RNA-Directed DNA Polymerase; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D006657:Histones; D050794:STAT1 Transcription Factor; D014764:Viral Proteins; D016899:Interferon-beta; D007371:Interferon-gamma; C000606502:DTX3L protein, mouse; D044767:Ubiquitin-Protein Ligases; C529384:Parp9 protein, mouse; D011065:Poly(ADP-ribose) Polymerases; D012194:RNA-Directed DNA Polymerase; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases