Proteasomal ubiquitin-mediated protein degradation is essential for maintaining cellular homeostasis. E3 ubiquitin ligases themselves are subject to regulation by degradation, either through self-ubiquitylation or targeting by exogenous E3 ligases in trans. GP78 is a RING finger ligase that has been implicated in ER-associated degradation (ERAD) of misfolded proteins and in mitophagy, suggesting it might have a role in quality control of depolarised mitochondria. In their work on page , Rukmini Mukherjee and Oishee Chakrabarti now show that GP78 itself is controlled through ubiquitylation by the cytosolic E3 ligase mahogunin RING Finger 1 (MGRN1). They show here that MGRN1 interacts with and ubiquitylates GP78 through non-canonical residue K11 linkages; this keeps GP78 levels low in healthy cells, thus preventing mitophagy. Mechanistically, the authors demonstrate that increased levels of Ca2+ upon mitochondrial stress disrupt the interaction between GP78 and MGRN1, thereby resulting in high levels of GP78 and mitophagy. In agreement with this, cells in which MGRN1 has been depleted have a larger number of depolarised mitochondria and a propensity for mitophagy. The authors also show that compromising MGRN1, which has been implicated in neurodegenerative disease, in the presence of disease-causing prion protein (PrP) interferes with GP78 ubiquitylation and mitochondrial quality control, thus suggesting a possible mechanism through which MGRN1 might contribute to neurodegeneration in a subset of familial prion diseases.
