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PreprintCited by 10Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysCellular transport and secretion

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Ubr1-induced selective endo-phagy/autophagy protects against the endosomal and Ca 2+ -induced proteostasis disease stress

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Wang, Ben B., Xu, Haijin, Isenmann, Sandra, Huang, Cheng, Elorza-Vidal, Xabier, Rychkov, Grigori Y, Estévez, Raúl, Schittenhelm, Ralf B., Lukacs, Gergely L., Apaja, Pirjo M.·2021·Cellular and Molecular Life Sciences
DOI 10.1101/2021.10.05.463117PMC PMC8888484

Preprint — published as 10.1007/s00018-022-04191-8 · Paper page

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Abstract

The defence mechanisms against endo-lysosomal homeostasis stress remain incompletely understood. Here, we identify Ubr1 as a protein quality control (QC) ubiquitin ligase that counteracts proteostasis stress by enhancing cargo selective autophagy for lysosomal degradation. Astrocyte regulatory cluster membrane protein MLC1 mutations increased intracellular Ca 2+ and caused endosomal compartment stress by fusion and enlargement. Endosomal protein QC pathway using ubiquitin QC ligases CHIP and Ubr1 with ESCRT-machinery was able to target only a fraction of MLC1-mutants for lysosomal degradation. As a consequence of the endosomal stress, we found an alternative QC route dependent on Ubr1, SQSTM1/p62 and arginylation to bypass MLC1-mutants to endosomal autophagy (endo-phagy). Significantly, this unfolded a general biological endo-lysosomal QC pathway for arginylated Ubr1-SQSTM1/p62 autophagy targets during Ca 2+ -assault. Conversely, the loss of Ubr1 with the absence of arginylation elicited endosomal compartment stress. These findings underscore the critical housekeeping role of Ubr1-dependent endo-phagy/autophagy in constitutive and provoked endo-lysosomal proteostasis stress, and link Ubr1 to Ca 2+ -homeostasis and proteins implicated in various diseases including cancers and brain disorders.

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Metadata

Authors
Wang, B. B., Xu, H., Isenmann, S., Huang, C., Elorza-Vidal, X., Rychkov, G. Y., Estévez, R., Schittenhelm, R. B., Lukacs, G. L., & Apaja, P. M.
Affiliations
  • EMBL Australia (AU)
  • McGill University (CA)
  • Monash University (AU)
  • South Australian Health and Medical Research Institute (AU)
  • Instituto de Salud Carlos III (ES)
  • Flinders University (AU)
Corresponding author
Apaja, Pirjo M.
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
openRxiv
Published
2021-10-05
Volume
79
Issue
3
Pages
167-167
ISSN
1420-682X (ISSN-L)
DOI
10.1101/2021.10.05.463117
PMC
PMC8888484
OpenAlex
W4220788803
Cited by
10
References
1
Citations by year
2025: 1 · 2024: 4 · 2023: 3 · 2022: 2
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
Funders
  • California Institute of Technology
  • EMBL Australia
  • Flinders University
  • Pohang University of Science and Technology
  • Seoul National University
  • Canadian Institutes of Health Research (173342_1, PJT153095)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
UBR1, selective autophagy, lysosomal stress, protein quality control, E3 ubiquitin ligase, MLC1, CHIP, p62, ESCRT, arginylation, calcium homeostasis, proteostasis, astrocytes, endolysosomal degradation
MeSH terms
Proteostasis, Animals, Arginine, Autophagy, Calcium, Cricetulus, HeLa Cells, Humans, Lysosomes, Endosomes, Signal Transduction, CHO Cells, Ubiquitin, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteolysis

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