MGRN1 in development and disease: a unifying view of a versatile membrane-tethered E3 ubiquitin ligase

Mahogunin Ring Finger 1 (MGRN1) is a multifunctional E3 ubiquitin ligase with broad biological significance and belongs to a small group of membrane-tethered E3s capable of regulating signaling receptors at the plasma membrane. Studies in mice first revealed its physiological importance, as loss of Mgrn1 leads to a wide range of phenotypes, including abnormal pigmentation, congenital malformations, and neurodegeneration. Remarkably, MGRN1 localizes to multiple cellular compartments, including the plasma membrane, mitochondria, nucleus, and endo-lysosomal pathway. MGRN1 is also involved in several cellular processes, including receptor regulation, protein homeostasis, and mitochondrial maintenance. While studies have emphasized the importance of MGRN1, it has been difficult to define unifying principles governing its function. In the present review, we summarize and integrate published findings to develop a clearer picture of MGRN1's roles, focusing on phenotypes observed in mouse models and the signaling pathways MGRN1 regulates. We propose shared mechanistic themes that reconcile the functional diversity of this unique E3 ligase, highlight gaps in the current literature, and identify areas for further investigation to better understand MGRN1's role in disease and evaluate its potential relevance for targeted protein degradation strategies.