Work

E3 ligase AREL1 controls perinuclear localization of lysosomes and supports Purkinje cell survival

Year: 2025

Type: article

Abstract: Localization of lysosomes influences their properties, e.g., perinuclear lysosomes are more acidic but less mobile compared with the peripheral ones. Furthermore, the endoplasmic reticulum (ER) can actively regulate the dynamics and functions of lysosomes via membrane contact sites. In this study, we find that ER-resident apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1) establishes membrane contacts with lysosomes by directly interacting with the V o a subunit of V-ATPase. AREL1 also catalyzes K33-linked polyubiquitylation of V-ATPase V 1 B2 subunit, inducing its binding to UBAC2 localized in the perinuclear ER. Depletion of AREL1 or UBAC2 increases the number of peripheral lysosomes that possess partially assembled V-ATPase, elevated luminal pH, and attenuated degradative capacity. Knockdown of ZRANB1, the deubiquitylating enzyme that antagonizes AREL1-mediated V 1 B2 ubiquitylation, promotes perinuclear clustering of lysosomes and increases lysosomal acidity and degradation. Mice lacking Arel1 exhibit age-dependent Purkinje cell loss, an ataxic phenotype, and motor impairment. Lipofuscin accumulation in the residual Purkinje cells of Arel1 −/− mice indicates lysosomal dysfunction. Orchestration of lysosomal positioning and function by the AREL1–UBAC2–V-ATPase axis underscores the physiological significance of ER-regulated perinuclear lysosomal positioning in neurons.

Source: The EMBO Journal

DOI: 10.1038/s44318-025-00654-3