Functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase. Involved in innate immune defense against viruses by mediating ubiquitination of DDX58 and IFIH1 (By similarity). Mediates 'Lys-63'-linked polyubiquitination of the DDX58 N-terminal CARD-like region and may play a role in signal transduction that leads to the production of interferons in response to viral infection (By similarity). Mediates 'Lys-63'-linked polyubiquitination of IFIH1 (By similarity). Promotes ISGylation of 14-3-3 sigma (SFN), an adapter protein implicated in the regulation of a large spectrum signaling pathway. Mediates estrogen action in various target organs (By similarity). Mediates the ubiquitination and subsequent proteasomal degradation of ZFHX3 (By similarity). Plays a role in promoting the restart of stalled replication forks via interaction with the KHDC3-OOEP scaffold and subsequent ubiquitination of BLM, resulting in the recruitment and retainment of BLM at DNA replication forks (PubMed:29125140). S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. ATP + [ISG15] + [protein]-lysine = AMP + diphosphate + [protein]-N-ISGyllysine. Protein modification; protein ubiquitination. Interacts (via SPRY domain) with DDX58 (via CARD domain). Interacts with ZFHX3. Interacts with NLRP12; this interaction reduces the E3 ubiquitin ligase TRIM25-mediated 'Lys-63'-linked DDX58 activation. Interacts with the KHDC3/FILIA-OOEP/FLOPED scaffold complex and BLM at DNA replication forks (PubMed:29125140). Interacts with RTN3; this interaction prevents DDX58 ubiquitination (By similarity). Localized to DNA replication forks. Ubiquitous. The RING-type zinc finger is important for ISG15 E3 ligase activity and autoISGylation. AutoISGylation negatively regulates ISG15 E3 ligase activity. The C-terminal B30.2/SPRY domain interacts with the first N-terminal CARD domain of DDX58. Auto-ISGylated.