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 (PubMed:22431752, PubMed:33711283). Mediates 'Lys-63'-linked polyubiquitination of HSP90AA1 which leads to its intracellular localization and reduced secretion (PubMed:22431752). Negatively regulating HSP90AA1 secretion in cranial mesenchyme cells impairs their emigration and is consequently essential for the correct development of the cranial neural folds and neural tube closure (PubMed:17442300, PubMed:22431752). Catalyzes ubiquitination and degradation of ZNF622, an assembly factor for the ribosomal 60S subunit, in hematopoietic cells, thereby promoting hematopoietic stem cell renewal (PubMed:33711283). 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. Protein modification; protein ubiquitination. Interacts with IGSF1 (By similarity). Ubiquitously expressed throughout early development of the embryo. Perinatal lethality, exencephaly, impaired neural fold elevation, abnormal head mesenchyme morphology and defects in eye and cranial vault morphology (PubMed:17442300, PubMed:22431752). Cranial mesenchyme (CM) cells are larger, have an abnormal shape and an abnormal emigration (PubMed:22431752). It is likely that the increased motility of CM cells results in the exencephaly phenotype (PubMed:22431752). Mice with a conditional deletion in hematopoietic cells show reduced hematopoietic stem cell frequency and protein translational rate upon proliferative stress, causing defects in transplantation ability and ex vivo maintenance (PubMed:33711283). Belongs to the UPL family. K-HECT subfamily.