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Mitophagy antagonism by Zika virus reveals Ajuba as a regulator of PINK1-Parkin signaling, PKR-dependent inflammation, and viral invasion of tissues

Sanket S. Ponia, Shelly J. Robertson, Kristin L. McNally, Gail L. Sturdevant, Matthew Lewis, Forrest Jessop, Catherine M. Bosio, Catherine Kendall, Dylan Gallegos, Arielle Hay, Cindi Schwartz, Rebecca Rosenke, Greg Saturday, Craig Martens, Sonja M. Best
doi: https://doi.org/10.1101/2021.01.29.428870
Sanket S. Ponia
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Shelly J. Robertson
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Kristin L. McNally
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Gail L. Sturdevant
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Matthew Lewis
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Forrest Jessop
2Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Catherine M. Bosio
2Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Catherine Kendall
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
3School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
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Dylan Gallegos
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Arielle Hay
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Cindi Schwartz
4Research Technology Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Rebecca Rosenke
5Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Greg Saturday
5Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Craig Martens
4Research Technology Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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Sonja M. Best
1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840
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  • For correspondence: sbest@niaid.nih.gov
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ABSTRACT

Dysregulated inflammation dominated by chemokine expression is a key feature of disease following infection with the globally important human pathogens, Zika virus (ZIKV) and dengue virus, but a mechanistic understanding of how pro-inflammatory responses are initiated is lacking. Mitophagy is a quality control mechanism that regulates innate immune signaling and cytokine production through selective degradation of damaged mitochondria. Here, we demonstrate that ZIKV NS5 antagonizes mitophagy by binding to the host protein Ajuba and preventing its translocation to depolarized mitochondria where it is required for PINK1 activation and downstream signaling. Consequent mitophagy suppression amplified the production of pro-inflammatory chemokines through PKR sensing of mitochondrial RNA. In Ajuba−/− mice, ZIKV induced early expression of pro-inflammatory chemokines associated with significantly enhanced dissemination to tissues. This work identifies Ajuba as a critical regulator of mitophagy, and demonstrates a role for mitophagy in limiting systemic inflammation following infection by globally important human viruses.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted January 30, 2021.
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Mitophagy antagonism by Zika virus reveals Ajuba as a regulator of PINK1-Parkin signaling, PKR-dependent inflammation, and viral invasion of tissues
Sanket S. Ponia, Shelly J. Robertson, Kristin L. McNally, Gail L. Sturdevant, Matthew Lewis, Forrest Jessop, Catherine M. Bosio, Catherine Kendall, Dylan Gallegos, Arielle Hay, Cindi Schwartz, Rebecca Rosenke, Greg Saturday, Craig Martens, Sonja M. Best
bioRxiv 2021.01.29.428870; doi: https://doi.org/10.1101/2021.01.29.428870
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Mitophagy antagonism by Zika virus reveals Ajuba as a regulator of PINK1-Parkin signaling, PKR-dependent inflammation, and viral invasion of tissues
Sanket S. Ponia, Shelly J. Robertson, Kristin L. McNally, Gail L. Sturdevant, Matthew Lewis, Forrest Jessop, Catherine M. Bosio, Catherine Kendall, Dylan Gallegos, Arielle Hay, Cindi Schwartz, Rebecca Rosenke, Greg Saturday, Craig Martens, Sonja M. Best
bioRxiv 2021.01.29.428870; doi: https://doi.org/10.1101/2021.01.29.428870

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