MARCHF6

Endoplasmic reticulum membrane-associated E3 ubiquitin ligase that plays a critical role in mitigating endoplasmic reticulum stress, the regulation of cholesterol and lipid homeostasis, and ferroptosis. Acts as a pivotal component of both the Ac/N-degron pathway (targeting the N-terminal acetyl group of substrates) and the ER-associated protein degradation-cytosol (ERAD-C) pathway (targeting misfolded substrates). For instance, mediates the degradation of Ac/N-degron-bearing proteins such as the G protein regulator RGS2 and the lipid droplet protein PLIN2. Suppresses endoplasmic reticulum stress and ferroptosis through cytosolic POMC degradation (By similarity). Prevents ferroptosis by acting as a NADPH sensor during lipid peroxidation through its C-terminal regulatory region. Facilitates also the degradation of selected endoplasmic reticulum proteins by associating with signal peptide peptidase for the turnover of endogenous tail-anchored proteins. Promotes ubiquitination of DIO2, leading to its degradation. By ubiquitinating and thereby modulating the stability of many proteins of the cholesterol pathway including SQLE, CYP51A1, CYP11A1 and HMGCR, acts as a crucial post-translational regulator of cholesterol synthesis..

Function from UniProtKB (O60337), read 2026-09-23. CC BY 4.0.