Regulation of the ISG15 activity by SUMO

Abstract

ISG15 is a Ubiquitin-like protein that plays important functions in different pathologies but these functions depend on the specie, cell type, viral type and ISG15 form. How ISG15 activities are regulated is unclear. Here we show that ISG15 can be SUMOylated and interacts with SUMO in a non-covalent manner. SUMOylation of ISG15 is triggered by different types of stress as well as upon overexpression of the tumor suppressor p14ARF. We show that ISG15 can be detected at the PML-NBs and that mutation of the SUMO binding sites positively modulates its co-localization with PML-NBs. Finally, we show that the interaction of SUMO with ISG15 positively modulates the anti-apoptotic activity of ISG15 upon IFN treatment, the pro-viral activity of ISG15 during VSV infection, and is required for proper mitochondria biogenesis.