Journal Article

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

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

2015

Overview

Holtzman and colleagues identify PARP9-DTX3L as an E3 ubiquitin ligase complex that interacts with STAT1 to modify chromatin accessibility for expression in interferon-stimulated genes and to target viral proteases for degradation. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/95 / 14 / 14/19 / 38 / 38/61 / 3C Viral Proteases / 42 / 64 / 64/60 / 692/420 / 692/420/2780 / 692/420/2780/262 / 82 / 82/16 / 82/29 / 82/79 / 82/83 / 9/10 / 96/109 / 96/95 / Animal genetic engineering / Animals / Antiviral agents / Biological response modifiers / Biomedicine / Cell Line / Cell Nucleus - metabolism / Cells (Biology) / Chromatin / Cysteine Endopeptidases - metabolism / Encephalomyocarditis virus - physiology / Gene expression / Genes / Genetic engineering / Health aspects / HEK293 Cells / Histones / Histones - metabolism / Host-Pathogen Interactions / Humans / Immunoblotting / Immunology / Infection control / Infectious Diseases / Interferon / Interferon-beta - pharmacology / Interferon-gamma - pharmacology / Ligases / Mice, Inbred C57BL / Mice, Transgenic / Microscopy, Confocal / Mutation / Poly(ADP-ribose) Polymerases - genetics / Poly(ADP-ribose) Polymerases - metabolism / Proteases / Protein Binding / RNA Interference / RNA-Directed DNA Polymerase / Scientific equipment industry / Signal Transduction / Stat1 protein / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - metabolism / Toxicity / Transcriptome - drug effects / Transgenic mice / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Viral Proteins - metabolism