Regulation of reticulophagy by the N-degron pathway

Ji, Chang Hoon; Kim, Hee Yeon; Heo, Ah Jung; Lee, Min Ju; Park, Daniel Youngjae; Kim, Dong Hyun; Kim, Bo Yeon; Kwon, Yong Tae

doi:10.1080/15548627.2019.1695402

Cited by 16 publications

(12 citation statements)

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“…Additional post-translational modifications by sumoylation, phosphorylation or arginylation with ubiquitination may modulate PQC signaling in a substrate-specific manner [15][16][17][18]. From these, arginylation has a role outside QC as N-terminal degron in fast proteasomal degradation of N-recognin type proteins [19].…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Isenmann

et al. 2022

Cell. Mol. Life Sci.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Wang

Isenmann

et al. 2022

Cell. Mol. Life Sci.

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“…Amplified mitophagy relies on both phosphorylation and ubiquitination by PINK1 and QC E3ligase Parkin in Parkinson's disease 14 . The alpha-1 antitrypsin variant was sequestered as a ubiquitinated and arginylated complex by SQSTM1/P62 for ER-phagy 15,16 . Selective endophagy requires sequential ubiquitin-arginine modifications and is likely initiated at Rab11A+ early endosomes with the association of PI3P and Rab11A by WIPI2 and the recruitment of ATG16L1 22 .…”

Section: Discussionmentioning

confidence: 99%

“…Additional post-translational modifications by sumoylation, phosphorylation or arginylation with ubiquitination may enrich PQC signalling in a substrate-specific manner [13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Isenmann

et al. 2021

Preprint

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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.

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“…TRIM22 positively regulated beclin 1 in macrophages infected with mycobacterium tuberculosis via nuclear factor‐κB (NF‐κB) signaling (Lou et al, 2018). TRIM13 underwent auto‐ubiquitination and interacted with p62 to form the oligomerized TRIM13‐p62 complexes, and then, led to lysosomal degradation during endoplasmic reticulum (ER) stress (Ji et al, 2020). TRIM16 interacted with ATG16L1 and guided the placement of ATG16L1 on damaged membranes to protect cells from mycobacterium tuberculosis invasion (Chauhan et al, 2016).…”

Section: Regulation Of Autophagy By Trim Proteinsmentioning

confidence: 99%

“…TRIM16 has been reported to enhance IL‐1β secretion (Munding et al, 2006). TRIM16 modulated Nrf2 antioxidant signaling (Ren et al, 2020), and TRIM13, the ER transmembrane E3s, recruited p62 to form a complex to alleviate ER stress (Ji et al, 2020). Collectively, some TRIM family proteins closely relate to the pathogenesis of DM and diabetic complications; their role in DM and its complications requires further research.…”

Section: Trim Proteins In Dm and Diabetic Complicationsmentioning

confidence: 99%

The role of TRIM family proteins in autophagy, pyroptosis, and diabetes mellitus

Wan

2021

Cell Biology International

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The ubiquitin‐proteasome system, which is one of the systems for cell protein homeostasis and degradation, happens through the ordered and coordinated action of three types of enzymes, E1 ubiquitin‐activating enzyme, E2 ubiquitin‐carrier enzyme, E3 ubiquitin‐protein ligase. Tripartite motif‐containing (TRIM) family proteins are the richest subfamily of really interesting new gene E3 ubiquitin ligases, which play a critical role not only in many biological processes, including proliferation, apoptosis, pyroptosis, innate immunity, and autophagy, but also many diseases like cancer, diabetes mellitus, and neurodegenerative disease. Increasing evidence suggests that TRIM family proteins play a vital role in modulating autophagy, pyroptosis, and diabetes mellitus. The aim of this review is to discuss the role of TRIM proteins in the regulation of autophagy, pyroptosis, diabetes mellitus, and diabetic complications.

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Regulation of reticulophagy by the N-degron pathway

Cited by 16 publications

References 1 publication

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

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

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

The role of TRIM family proteins in autophagy, pyroptosis, and diabetes mellitus

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Regulation of reticulophagy by the N-degron pathway

Cited by 16 publications

References 1 publication

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

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

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

The role of TRIM family proteins in autophagy, pyroptosis, and diabetes mellitus

Contact Info

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