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

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

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162 Scopus citations

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 language	English
Pages (from-to)	1215-1227
Number of pages	13
Journal	Nature immunology
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/ni.3279
State	Published - Dec 1 2015

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Zhang, Y., Mao, D., Roswit, W. T., Jin, X., Patel, A. C., Patel, D. A., Agapov, E., Wang, Z., Tidwell, R. M., Atkinson, J. J., Huang, G., McCarthy, R., Yu, J., Yun, N. E., Paessler, S., Lawson, T. G., Omattage, N. S., Brett, T. J., & 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

@article{bd6eadcde4d64eb5aa2c1bba8713b999,

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

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.",

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

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year = "2015",

month = dec,

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doi = "10.1038/ni.3279",

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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

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T1 - PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection

AU - Zhang, Yong

AU - Mao, Dailing

AU - Roswit, William T.

AU - Jin, Xiaohua

AU - Patel, Anand C.

AU - Patel, Dhara A.

AU - Agapov, Eugene

AU - Wang, Zhepeng

AU - Tidwell, Rose M.

AU - Atkinson, Jeffrey J.

AU - Huang, Guangming

AU - McCarthy, Ronald

AU - Yu, Jinsheng

AU - Yun, Nadezhda E.

AU - Paessler, Slobodan

AU - Lawson, T. Glen

AU - Omattage, Natalie S.

AU - Brett, Tom J.

AU - Holtzman, Michael J.

PY - 2015/12/1

Y1 - 2015/12/1

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

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