Unraveling the Physiological Role of Mitophagy in Flaviviruses-Host Interactions

Autophagy is a catabolic process that eliminates the intracellular material to promote nutrient recycling and organelle regeneration, thus maintaining cellular homeostasis. In addition to serve as a bulk degradation process, mounting lines of evidence highlight that autophagy can selectively sequestrate degradative cargos (known as “selective autophagy”), such as damaged organelles and aggregated proteins through specific cargo receptors, and deliver them to autophagic process for degradation. Several flaviviruses, including hepatitis C virus (HCV) and dengue virus (DENV) have been shown to induce autophagy to promote virus replication in the infected cells. However, whether flavivirus infection activates selective autophagy to regulate virus-host interactions still remains unclear. Recently, we found that DENV and Zika virus (ZIKV) activate selective autophagy through multiple cargo receptors-mediated degradation process. The DENV- and ZIKV-induced selective autophagy was shown to degrade mitochondria, refered to as “mitophagy” in the infected cells, accompanied by protein phosphorylations of specific cargo receptors. Also, the cell live imaging analysis demosntrated the engulfment process of mitochondria by the viral-triggered mitophagy in DENV- and ZIKV-infected cells. In addition, the sequestration of mitochondria by DENV- and ZIKV-activated mitophagic process was further confirmed by the correlative light and electron microscopy-based ultrastructural imaging analysis of the infected cells. Collectively, these results imply that flavivirus infection may activate mitophagy through cargo receptor phosphorylation to promote mitochondrial turnover in the infected cells. So far, the molecular process underlying how flavivirus activates mitophagy to regulate viral growth and host cell response is largely unknown. Thus, this three-year research proposal is aim to uncover the detailed molecular mechanism of how flavivirus activates mitophagy via cargo receptor phosphorylation to regulate flavivirus-host interactions. To this end, three specific aims are proposed as the follows: Aim I: To study how flavivirus infection activates mitophagy. Aim II: To investigate how flavivirus infection induces cargo receptor phosphorylation to regulate mitophagy.Aim III: To uncover the physiological significance of mitophagy in flaviviruses-host interactions.Successful accomplishment of this research proposal will not only promote us to delineate the molecular basis of how flaviviruses regulate cargo receptor phosphorylation to activte mitpophagy, but also to unveil how mitophagy modulates flavivirus-host interactions.

Project ID:PC10907-1332
External Project ID:MOST109-2320-B182-010-MY3