Asunto(s)
Antivirales , Citarabina/análogos & derivados , Virus del Dengue/efectos de los fármacos , Dengue/tratamiento farmacológico , Estomatitis Vesicular/tratamiento farmacológico , Vesiculovirus/efectos de los fármacos , Animales , Antivirales/administración & dosificación , Antivirales/farmacología , Virus del Dengue/fisiología , Células HEK293 , Humanos , Ratones Endogámicos C57BL , Vesiculovirus/fisiología , Replicación Viral/efectos de los fármacosRESUMEN
The ER tethers tightly to mitochondria and the mitochondrial protein FUNDC1 recruits Drp1 to ER-mitochondria contact sites, subsequently facilitating mitochondrial fission and preventing mitochondria from undergoing hypoxic stress. However, the mechanisms by which the ER modulates hypoxia-induced mitochondrial fission are poorly understood. Here, we show that USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites under hypoxia and promotes hypoxia-induced mitochondrial division. In response to hypoxia, USP19 binds to and deubiquitinates FUNDC1 at ER-mitochondria contact sites, which facilitates Drp1 oligomerization and Drp1 GTP-binding and hydrolysis activities, thereby promoting mitochondrial division. Our findings reveal a unique hypoxia response pathway mediated by an ER protein that regulates mitochondrial dynamics.