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Published on: April 24, 2021
Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease
Ben B Wang1,2, Haijin Xu3, Sandra Isenmann1,2
1Lifelong Health, Organelle Proteostasis Diseases, South Australian Health and Medical Research Institute (SAHMRI), 5000 North Terrace, Adelaide, SA, 5000, Australia.
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.
Insights
Ubr1, a ubiquitin ligase, combats endo-lysosomal stress by promoting selective autophagy. This pathway clears damaged proteins, like MLC1 mutants, and is crucial for cellular proteostasis and calcium homeostasis.
Area of Science:
- Cellular Biology
- Biochemistry
- Molecular Biology
Background:
- Cellular defense against endo-lysosomal stress is not fully understood.
- Mutations in MLC1 cause endosomal stress in astrocytes.
- Protein quality control (QC) mechanisms are vital for maintaining cellular proteostasis.
Purpose of the Study:
- To identify novel protein quality control mechanisms involved in endo-lysosomal stress.
- To elucidate the role of Ubr1 in counteracting proteostasis perturbations.
- To investigate the link between Ubr1, arginylation, and endosomal autophagy.
Main Methods:
- Utilized genetic and biochemical approaches to study protein degradation pathways.
- Investigated the function of Ubr1 in selective autophagy and endosomal QC.
- Analyzed the impact of MLC1 mutations and Ubr1 loss on endosomal compartment integrity.
Main Results:
- Identified Ubr1 as an E3 ubiquitin ligase that facilitates endosomal cargo-selective autophagy.
- Demonstrated that Ubr1 and CHIP mediate partial lysosomal clearance of mutant endosomal MLC1.
- Showcased Ubr1 and SQSTM1/p62-dependent targeting of ubiquitinated and arginylated MLC1 mutants for endophagy.
- Revealed that loss of Ubr1 or arginylation leads to endosomal compartment stress.
- Found that this QC pathway is activated during cytosolic Ca2+-assault.
Conclusions:
- Ubr1 plays a critical housekeeping role in endo-lysosomal proteostasis through arginylation-dependent endophagy/autophagy.
- Ubr1 is essential for clearing damaged endosomal cargo, including MLC1 mutants.
- The study suggests a connection between Ubr1, calcium homeostasis, and diseases like cancer and brain disorders.
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