2026-04-17T03:13:27Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1845422025-11-20T13:51:21Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Wang, Ben B. author Xu, Haijin author Isenmann, Sandra author Huang, Cheng author Elorza Vidal, Xabier author Rychkov, Grigori Y. author Estévez Povedano, Raúl author Schittenhelm, Ralf B. author Lukacs, Gergely L. author Apaja, Pirjo M. author 2022-03-31T12:44:53Z 2022-03-31T12:44:53Z 2022-03 2022-03-31T12:44:53Z The cellular defense mechanisms against cumulative endo-lysosomal stress remain incompletely understood. Here, we iden tify Ubr1 as a protein quality control (QC) E3 ubiquitin-ligase that counteracts proteostasis stresses by facilitating endosomal cargo-selective autophagy for lysosomal degradation. Astrocyte regulatory cluster membrane protein MLC1 mutations cause endosomal compartment stress by fusion and enlargement. Partial lysosomal clearance of mutant endosomal MLC1 is accomplished by the endosomal QC ubiquitin ligases, CHIP and Ubr1 via ESCRT-dependent route. As a consequence of the endosomal stress, a supportive QC mechanism, dependent on both Ubr1 and SQSTM1/p62 activities, targets ubiquit inated and arginylated MLC1 mutants for selective endosomal autophagy (endophagy). This QC pathway is also activated for arginylated Ubr1-SQSTM1/p62 autophagy cargoes during cytosolic Ca2+-assault. Conversely, the loss of Ubr1 and/or arginylation elicited endosomal compartment stress. These fndings underscore the critical housekeeping role of Ubr1 and arginylation-dependent endophagy/autophagy during endo-lysosomal proteostasis perturbations and suggest a link of Ubr1 to Ca2+ homeostasis and proteins implicated in various diseases including cancers and brain disorders Autofàgia Lisosomes Càncer Proteïnes Autophagy Lysosomes Cancer Proteins Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease stress