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. Epub 2015 Oct 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Cysteine Endopeptidases / metabolism*
  • Encephalomyocarditis virus / physiology
  • HEK293 Cells
  • Histones / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Immunoblotting
  • Interferon-beta / pharmacology
  • Interferon-gamma / pharmacology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Mutation
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Binding
  • RNA Interference
  • RNA-Directed DNA Polymerase
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Transcriptome / drug effects
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Viral Proteins / metabolism*

Substances

  • Histones
  • STAT1 Transcription Factor
  • Viral Proteins
  • Interferon-beta
  • Interferon-gamma
  • DTX3L protein, mouse
  • Ubiquitin-Protein Ligases
  • Parp9 protein, mouse
  • Poly(ADP-ribose) Polymerases
  • RNA-Directed DNA Polymerase
  • Cysteine Endopeptidases
  • 3C proteases

Associated data

  • GEO/GSE61411
  • GEO/GSE61413
  • GEO/GSE61414
  • GEO/GSE61421