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 Ca2+ 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 Ca2+-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 Ca2+-homeostasis and proteins implicated in various diseases including cancers and brain disorders.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- α
- anti
- CHIP
- C-terminus of Hsc70-Interacting Protein
- cs
- cell surface
- ER
- endoplasmic reticulum
- ERAD
- endoplasmic reticulum-associated degradation
- ESCRT
- endosomal sorting complex required for transport
- GlialCAM
- glial cell adhesion molecule
- IP
- immunoprecipitation
- LAMP1
- lysosomal associated membrane protein 1
- MLC1
- megalencephalic leukoencephalopathy with subcortical cyst
- ns
- non-significant
- NT
- non-target
- PM
- plasma membrane
- PQC
- protein quality control
- siRNA
- small interfering RNA
- Ub
- ubiquitin
- Ubr1
- ubiquitin-protein ligase E3 component n-recognin 1.