Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease stress

Ben B. Wang, Haijin Xu, Sandra Isenmann, Cheng Huang, Xabier Elorza-Vidal, Grigori Y. Rychkov, Raúl Estévez, Ralf B. Schittenhelm, Gergely L. Lukacs, Pirjo M. Apaja

Research output: Contribution to journalArticlepeer-review

Abstract

The cellular defense mechanisms against cumulative endo-lysosomal stress remain incompletely understood. Here, we identify 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 ubiquitinated 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 findings 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.

Original languageEnglish
Article number167
Number of pages22
JournalCellular and Molecular Life Sciences
Volume79
Issue number3
DOIs
Publication statusPublished - Mar 2022

Keywords

  • Lysosome
  • Protein homeostasis network
  • Protein stability
  • Regeneration
  • Reprogramming
  • Stress response

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