2. Academic Validation
  3. PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection

PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection

  • Nat Immunol. 2015 Dec;16(12):1215-27. doi: 10.1038/ni.3279.
Yong Zhang 1,  Dailing Mao 1,  William T Roswit 1,  Xiaohua Jin 1,  Anand C Patel 1 2,  Dhara A Patel 1,  Eugene Agapov 1,  Zhepeng Wang 1,  Rose M Tidwell 1,  Jeffrey J Atkinson 1,  Guangming Huang 1,  Ronald McCarthy 1,  Jinsheng Yu 3,  Nadezhda E Yun 4,  Slobodan Paessler 4,  T Glen Lawson 5,  Natalie S Omattage 1,  Tom J Brett 1 6 7,  Michael J Holtzman 1 6
Affiliations

Affiliations

  • 1 Drug Discovery Program, Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 2 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 3 Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 4 Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
  • 5 Department of Chemistry, Bates College, Lewiston, Maine, USA.
  • 6 Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 7 Department of Biochemistry, Washington University School of Medicine, St. Louis, Missouri, USA.
PMID: 26479788 DOI: 10.1038/ni.3279
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.

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