E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; regulates POU5F1 protein level during differentiation of embryonal carcinoma cells (ECCs) but not in undifferentiated ECCs and embryonic stem cells (ESCs). Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation. 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. Activated by NDFIP1- and NDFIP2-binding. Protein modification; protein ubiquitination. Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts with ERBB4, NDFIP1 and NDFIP2. Interacts with ARRDC4 (By similarity). Interacts with POU5F1, RBP1, EGR2 and SLC11A2. Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates ARRDC1 (By similarity). Interacts (via WW domains) with ARRDC2 and ARRDC3 (By similarity). The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain. The WW domains mediate interaction with PPxY motif-containing proteins. Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome (By similarity). A cysteine residue is required for ubiquitin-thioester formation.