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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1215-1227
Number of pages13
JournalNature Immunology
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2015

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Virus Diseases
Ligases
Ubiquitin
Histones
Interferons
STAT1 Transcription Factor
Ubiquitin-Protein Ligases
Transgenic Mice
Antiviral Agents
Immunity
Peptide Hydrolases
Gene Expression
3C proteases

ASJC Scopus subject areas

  • Immunology

Cite this

Zhang, Y., Mao, D., Roswit, W. T., Jin, X., Patel, A. C., Patel, D. A., ... Holtzman, M. J. (2015). PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. Nature Immunology, 16(12), 1215-1227. https://doi.org/10.1038/ni.3279

PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. / Zhang, Yong; Mao, Dailing; Roswit, William T.; Jin, Xiaohua; Patel, Anand C.; Patel, Dhara A.; Agapov, Eugene; Wang, Zhepeng; Tidwell, Rose M.; Atkinson, Jeffrey J.; Huang, Guangming; McCarthy, Ronald; Yu, Jinsheng; Yun, Nadezhda E.; Paessler, Slobodan; Lawson, T. Glen; Omattage, Natalie S.; Brett, Tom J.; Holtzman, Michael J.

In: Nature Immunology, Vol. 16, No. 12, 01.12.2015, p. 1215-1227.

Research output: Contribution to journalArticle

Zhang, Y, Mao, D, Roswit, WT, Jin, X, Patel, AC, Patel, DA, Agapov, E, Wang, Z, Tidwell, RM, Atkinson, JJ, Huang, G, McCarthy, R, Yu, J, Yun, NE, Paessler, S, Lawson, TG, Omattage, NS, Brett, TJ & Holtzman, MJ 2015, 'PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection', Nature Immunology, vol. 16, no. 12, pp. 1215-1227. https://doi.org/10.1038/ni.3279
Zhang, Yong ; Mao, Dailing ; Roswit, William T. ; Jin, Xiaohua ; Patel, Anand C. ; Patel, Dhara A. ; Agapov, Eugene ; Wang, Zhepeng ; Tidwell, Rose M. ; Atkinson, Jeffrey J. ; Huang, Guangming ; McCarthy, Ronald ; Yu, Jinsheng ; Yun, Nadezhda E. ; Paessler, Slobodan ; Lawson, T. Glen ; Omattage, Natalie S. ; Brett, Tom J. ; Holtzman, Michael J. / PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. In: Nature Immunology. 2015 ; Vol. 16, No. 12. pp. 1215-1227.
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