mHERC6 is the essential ISG15 E3 ligase in the murine system.

Posttranslational protein modification by ubiquitin and ubiquitin-like modifiers (UBLs) is mediated by a hierarchical cascade of conjugating enzymes and affects multiple biological processes within the cell. Interferon-stimulated gene 15 (ISG15) is an UBL, which is strongly induced by type I Interferon and ISG15 modification was shown to play an essential role in antiviral defense. While hHERC5 is the major E3 ligase for ISG15 modification in humans, ISGylation in the murine systems at the level of E3 ligases was weakly characterized as rodent genomes lack a direct homologue of hHERC5. Here, we show that mHERC6 is strongly induced by different pathogen-associated molecular patterns (PAMPs) in a type I Interferon receptor (IFNAR1) dependent manner. We demonstrate that mHERC6 is essential for endogenous murine ISGylation and thus represents the dominant ISG15 E3 ligase in mice. In contrast to its human homologue, mHERC6 is also capable to mediate conjugation of human ISG15.