UBE2J2 is an ER-membrane-anchored ubiquitin-conjugating enzyme (E2) that catalyzes the covalent attachment of ubiquitin to target proteins, with particular importance in ER-associated degradation (ERAD) 1. Unlike most E2 enzymes that exclusively catalyze lysine ubiquitination, UBE2J2 possesses unique structural features enabling noncanonical serine ubiquitination through a two-layered mechanism involving active site rearrangement and a conserved histidine that activates substrate serines 2. UBE2J2 functions selectively in degrading specific misfolded ER proteins; it partners with the E3 ligase MARCH6 for cholesterol-stimulated degradation of squalene monooxygenase (SQLE), distinct from UBE2G2's role in HMGCR degradation 3. Critically, UBE2J2 acts as a lipid sensor, responding to membrane lipid saturation changes: loose lipid packing impairs ubiquitin loading and activity, while tight packing promotes its active conformation 1. Beyond ERAD, UBE2J2 participates in EVI/WLS ubiquitylation for WNT pathway regulation 4 and cooperates with GATOR2 to catalyze Lys-6-linked ubiquitination of NPRL2. Dysregulation of UBE2J2 has clinical relevance: it enhances venetoclax sensitivity in acute myeloid leukemia when depleted alongside MARCH5 5, and elevated UBE2J2 expression associates with poor colorectal cancer prognosis 6. Intriguingly, UBE2J2 itself undergoes proteasomal degradation, suggesting its steady-state levels regulate ER protein quality control 7.