E3 ubiquitin-protein ligase MARCHF6 (MARCHF6)

E3 ubiquitin-protein ligase MARCHF6 is a large, multi-pass transmembrane protein localized primarily to the endoplasmic reticulum membrane. It belongs to the membrane-associated RING-CH-type zinc finger family and functions as an E3 ubiquitin ligase, facilitating ubiquitination and proteasome-mediated degradation of substrate proteins. MARCHF6 is a key regulator of the Ac/N-degron pathway (recognizing N-terminally acetylated proteins for degradation) and ER-associated degradation (ERAD), involved in maintaining protein quality control, mitigating ER stress, and regulating lipid and cholesterol homeostasis. It plays a dual role in ferroptosis by targeting both pro- and anti-ferroptotic substrates, and its dysregulation is implicated in cancer, neurodegeneration, metabolic diseases, and certain epilepsies[1][2][3]. MARCHF6’s activity is being explored as a prospective therapeutic target via small molecule inhibitors, particularly in cancer and ferroptosis-related disorders.

Other names

Membrane-associated ring-CH-type finger 6MARCH6KIAA0597RNF176TEB4MARCH-VIDoa10 homologMembrane-associated RING finger protein 6Membrane-associated RING-CH protein VIProtein TEB-4RING finger protein 176RING-type E3 ubiquitin transferase MARCHF6FAME3FCMTE3

Modulation of ubiquitin ligase activity to alter protein degradation (including pro- or anti-ferroptotic substrate degradation)[1] Targeting Ac/N-degron recognition to influence ferroptosis and stress responses[1] Regulation of cholesterol synthesis by ubiquitinating cholesterol pathway enzymes[2]