TY - JOUR T1 - Mitophagy antagonism by Zika virus reveals Ajuba as a regulator of PINK1-Parkin signaling, PKR-dependent inflammation, and viral invasion of tissues JF - bioRxiv DO - 10.1101/2021.01.29.428870 SP - 2021.01.29.428870 AU - Sanket S. Ponia AU - Shelly J. Robertson AU - Kristin L. McNally AU - Gail L. Sturdevant AU - Matthew Lewis AU - Forrest Jessop AU - Catherine M. Bosio AU - Catherine Kendall AU - Dylan Gallegos AU - Arielle Hay AU - Cindi Schwartz AU - Rebecca Rosenke AU - Greg Saturday AU - Craig Martens AU - Sonja M. Best Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/30/2021.01.29.428870.abstract N2 - 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 StatementThe authors have declared no competing interest. ER -