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Antagonism of mitophagy by Zika virus reveals Ajuba as a regulator of PINK1-Parkin signaling and PKR-dependent inflammation

ABSTRACT: Dysregulated inflammation is a key driver of disease following infection with the globally important human pathogens, Zika virus (ZIKV) and dengue virus. However, specific mechanisms of inflammation are not well defined. Here, we demonstrate that ZIKV antagonizes mitophagy, or the process of selective degradation of damaged mitochondria. The mechanism of antagonism was through interactions between NS5 and the host protein Ajuba to prevent Ajuba translocation to depolarized mitochondria. We further identify a role of Ajuba in mitophagy through augmenting PINK1 kinase activity. Mitophagy suppression in infected Ajuba-/- cells amplified the cellular integrated stress response (ISR) to promote ZIKV replication, and increased pro-inflammatory cytokine expression dependent on the ISR kinase, PKR. Thus, ZIKV suppresses mitophagy to favor replication and this failure of mitochondrial quality control is translated to inflammation by PKR, suggesting new therapeutic targets to treat flavivirus disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE162688 | GEO | 2021/09/08

REPOSITORIES: GEO

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Antagonism of mitophagy by Zika virus reveals Ajuba as a regulator of PINK1-Parkin signaling and PKR-dependent inflammation

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