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

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 quali...

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Published in:Cell reports (Cambridge) 2021-10, Vol.37 (4), p.109888-109888, Article 109888
Main Authors: Ponia, Sanket S., Robertson, Shelly J., McNally, Kristin L., Subramanian, Gayatri, Sturdevant, Gail L., Lewis, Matthew, Jessop, Forrest, Kendall, Catherine, Gallegos, Dylan, Hay, Arielle, Schwartz, Cindi, Rosenke, Rebecca, Saturday, Greg, Bosio, Catherine M., Martens, Craig, Best, Sonja M.
Format: Article
Language:English
Subjects:
A549 Cells
Animals
chemokines
Chlorocebus aethiops
eIF-2 Kinase - genetics
eIF-2 Kinase - metabolism
flavivirus
HEK293 Cells
HeLa Cells
Humans
LIM Domain Proteins - genetics
LIM Domain Proteins - metabolism
Mice
Mice, Knockout
mitochondria
Mitophagy
mtRNA
Parkin
pathogenesis
PINK1
PKR
Protein Kinases - genetics
Protein Kinases - metabolism
Signal Transduction
Vero Cells
Zika virus
Zika Virus - genetics
Zika Virus - metabolism
Zika Virus Infection - genetics
Zika Virus Infection - metabolism
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Summary: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 nonstructural protein 5 (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 amplifies the production of pro-inflammatory chemokines through protein kinase R (PKR) sensing of mitochondrial RNA. In Ajuba−/− mice, ZIKV induces 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. [Display omitted] •Zika virus antagonizes mitophagy by inhibiting Ajuba translocation to mitochondria•Viral suppression of mitophagy amplifies proinflammatory chemokine expression•Chemokine expression is dependent on PKR sensing of mitochondrial dsRNA•Suppressed mitophagy amplifies early chemokines and viral tissue burden in vivo Inflammation characterized by chemokine expression is a key feature of Zika virus infection in humans. Here, Ponia et al. demonstrate that Zika virus antagonizes mitophagy. Retention of damaged mitochondria in infected cells amplifies chemokine expression by PKR-mediated sensing of mitochondrial dsRNA.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.109888