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Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues.
- Source :
-
Cell reports [Cell Rep] 2021 Oct 26; Vol. 37 (4), pp. 109888. - Publication Year :
- 2021
-
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 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 <superscript>-/-</superscript> 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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Published by Elsevier Inc.)
- Subjects :
- A549 Cells
Animals
Chlorocebus aethiops
HEK293 Cells
HeLa Cells
Humans
LIM Domain Proteins genetics
Mice
Mice, Knockout
Protein Kinases genetics
Vero Cells
Zika Virus genetics
Zika Virus Infection genetics
eIF-2 Kinase genetics
LIM Domain Proteins metabolism
Mitophagy
Protein Kinases metabolism
Signal Transduction
Zika Virus metabolism
Zika Virus Infection metabolism
eIF-2 Kinase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 37
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 34706234
- Full Text :
- https://doi.org/10.1016/j.celrep.2021.109888