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.
Highlights
Disease-causing mutations, as well as perturbations in intracellular Ca2+ homeostasis, may result in protein misfolding and/or accumulation in the cytosol or membrane organelles, mitochondrial oxidative damage [1], the endoplasmic reticulum (ER) stress or lysosomal swelling and exocytosis [2] that have been linked to numerous Mendelian disorders, neurodegenerative diseases, and cancers
We propose a role of the Ubr1/SQSTM1/p62axis in the endosomal protein quality control (PQC) mechanism protecting against cytosolic Ca2+-stress and endosomal accumulation of misfolded cargoes that may play a role in proteostasis diseases
These results indicate that the significantly reduced steady-state expression of megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1) mutants is attributed to their accelerated turnover in post-Golgi compartments
Summary
Disease-causing mutations, as well as perturbations in intracellular Ca2+ homeostasis, may result in protein misfolding and/or accumulation in the cytosol or membrane organelles, mitochondrial oxidative damage [1], the endoplasmic reticulum (ER) stress or lysosomal swelling and exocytosis [2] that have been linked to numerous Mendelian disorders, neurodegenerative diseases, and cancers. At the ER, QC mechanisms can recognize various degradation signals (degrons) in the luminal, transmembrane or cytosolic segments of misfolded membrane proteins as part of the ER-associated degradation (ERAD) and ER-phagy pathway [4, 5]. Defective cell surface membrane proteins generated either in situ or following their escape from the ER QC are recognized by the peripheral PQC machinery. Increased ubiquitin conjugation (ubiquitination) of non-native plasma membrane (PM) proteins can signal their internalization, as well as ESCRT (endosomal sorting complex required for transport)-dependent targeting to the multivesicular body (MVB) and lysosomal degradation [6–10]. The peripheral PQC has a critical role in maintaining native protein composition and intra- and inter-organelles membrane dynamics between Golgi, the plasma membrane (PM)- and endo-lysosomal compartments, even at the cost of exacerbating the loss-of-functional phenotype of misfolded but partially functional mutants (e.g [6, 7, 11–13])
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