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

Yong Zhang; Dailing Mao; William T Roswit; Xiaohua Jin; Anand C Patel; Dhara A Patel; Eugene Agapov; Zhepeng Wang; Rose M Tidwell; Jeffrey J Atkinson; Guangming Huang; Ronald McCarthy; Jinsheng Yu; Nadezhda E Yun; Slobodan Paessler; T Glen Lawson; Natalie S Omattage; Tom J Brett; Michael J Holtzman

doi:10.1038/ni.3279

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.

Authors

Yong Zhang¹, Dailing Mao¹, William T Roswit¹, Xiaohua Jin¹, Anand C Patel^{1

2}, Dhara A Patel¹, Eugene Agapov¹, Zhepeng Wang¹, Rose M Tidwell¹, Jeffrey J Atkinson¹, Guangming Huang¹, Ronald McCarthy¹, Jinsheng Yu³, Nadezhda E Yun⁴, Slobodan Paessler⁴, T Glen Lawson⁵, Natalie S Omattage¹, Tom J Brett^{1

6

7}, Michael J Holtzman^{1

6}

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
PMCID: PMC4653074
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.

Publication types

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

MeSH terms

3C Viral Proteases
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 Viral Proteases

Associated data

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding