E3 ubiquitin ligase that catalyzes the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate. In response to bacterial infection, negatively regulates the phagocyte oxidative burst by controlling the turnover of the NADPH oxidase complex subunits. Promotes monoubiquitination of CYBA and 'Lys-48'-linked polyubiquitination and degradation of CYBB NADPH oxidase catalytic subunits, both essential for the generation of antimicrobial reactive oxygen species. Involved in the maintenance of cholesterol homeostasis. In response to high sterol concentrations ubiquitinates HMGCR, a rate-limiting enzyme in cholesterol biosynthesis, and targets it for degradation. The interaction with INSIG1 is required for this function. In addition, triggers ubiquitination of SCAP, likely inhibiting its transport to the Golgi apparatus and the subsequent processing/maturation of SREBPF2, ultimately down-regulating cholesterol biosynthesis. 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. Interacts (via YLYF motif) with INSIG1 and INSIG2.