Order through destruction: how ER‐associated protein degradation contributes to organelle homeostasis

Christianson, John C.; Carvalho, Pedro

doi:10.15252/embj.2021109845

Cited by 88 publications

(79 citation statements)

References 133 publications

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“…These considerations lead us to propose that RNF26 switches between functional states to sustain dynamic regulation of ER-endosome and ER-cytoskeleton interactions. Within the ER membrane, toggling of RNF26 E3 ligase activity could be accommodated for instance by the availability of its cognate ubiquitin-loaded E2 enzyme UBE2J1 (Cremer et al, 2020a), which is extensively implicated in ER-associated protein degradation (ERAD) (Christianson & Carvalho, 2022, Oikonomou & Hendershot, 2020). Perinuclear integration of lysosomes with ER compartments that accommodate misfolded ER proteins suggest a functional connection between these two organelles.…”

Section: Discussionmentioning

confidence: 99%

Vimentin intermediate filaments organize organellar architecture in response to ER stress

Cremer

Voortman²,

Bos³

et al. 2022

Preprint

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Compartmentalization of organelles in space and time affects their functional state and enables higher order regulation of essential cellular processes. How organellar residence is maintained in a defined area of the cell remains poorly understood. In this study, we uncover a new role for intermediate filaments in the maintenance of organellar architecture and dynamics, which is executed through a functional connection between Vimentin and the ER-embedded ubiquitin ligase ring finger protein 26 (RNF26). While the ubiquitin ligase function of RNF26 promotes perinuclear positioning of endolysosomes, its catalytically inactive mutant I382R preferentially binds Vimentin through the RNF26 C-terminal tail. Loss of either RNF26 or Vimentin redistributes endolysosomes throughout the cytosol and mobilizes ER membranes from the perinuclear ER towards the periphery. Furthermore, RNF26 and Vimentin control changes in ER morphology and organelle compartmentalization during ER stress. Collectively, we define a new function for Vimentin-containing intermediate filaments as anchors of a dynamic interplay between the ER and endosomes, critical to the integrity of the perinuclear ER and corresponding perinuclear endosomal cloud during homeostatic and stress conditions.SynopsisThe perinuclear area hosts a wide variety of cellular organelles, and their interaction with the ER governs essential cellular processes. To spatiotemporally organize endosomes and ER in the perinuclear region, the ER-embedded E3 ubiquitin ligase RNF26 interacts with Vimentin to physically link the perinuclear ER membrane with the intermediate filament cytoskeleton. As a result, Vimentin ensures perinuclear RNF26 retention, which in turn controls the perinuclear location of ER membranes and endosomes, which can be affected during stressed conditions. Vimentin interacts with inactive RNF26 in the ER membraneRNF26 by virtue of the Vimentin interaction controls perinuclear organization of ER membranes and the endosomal systemVimentin immobilizes ER membranes in the perinuclear areaVimentin and RNF26 compartmentalize organelles in the perinuclear region during ER stressWe define a new function of Vimentin intermediate filaments in the control of the perinuclear endosomal and ER organization

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Section: Discussionmentioning

confidence: 99%

Vimentin intermediate filaments organize organellar architecture in response to ER stress

Cremer

Voortman²,

Bos³

et al. 2022

Preprint

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“…The central protein of the retrotranslocon channels is Hrd1, which forms a ubiquitin-gated protein-conducting channel [ 57 , 58 ]. Hrd1 is complexed with proteins located luminally—to enable the docking of targets—and a membrane-embedded ubiquitin ligase [ 59 ]. All ERAD branches converge in the cytosolic AAA-ATPase (Cdc48 in yeast; p97/VCP in mammals), which assists in the retrotranslocation process and passes the targets to the proteasome [ 59 ].…”

Section: Protein Degradation Controlled By Erdj3 Erdj4 and Erdj5mentioning

confidence: 99%

“…Hrd1 is complexed with proteins located luminally—to enable the docking of targets—and a membrane-embedded ubiquitin ligase [ 59 ]. All ERAD branches converge in the cytosolic AAA-ATPase (Cdc48 in yeast; p97/VCP in mammals), which assists in the retrotranslocation process and passes the targets to the proteasome [ 59 ]. The Sec61 translocon, which is the channel for protein import but, also, for cotranslational degradation (see above), is still under debate for the retrotranslocation of misfolded proteins.…”

Section: Protein Degradation Controlled By Erdj3 Erdj4 and Erdj5mentioning

confidence: 99%

Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum

Daverkausen-Fischer

Draga

Pröls

2022

IJMS

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The endoplasmic reticulum (ER) of mammalian cells is the central organelle for the maturation and folding of transmembrane proteins and for proteins destined to be secreted into the extracellular space. The proper folding of target proteins is achieved and supervised by a complex endogenous chaperone machinery. BiP, a member of the Hsp70 protein family, is the central chaperone in the ER. The chaperoning activity of BiP is assisted by ER-resident DnaJ (ERdj) proteins due to their ability to stimulate the low, intrinsic ATPase activity of BiP. Besides their co-chaperoning activity, ERdj proteins also regulate and tightly control the translation, translocation, and degradation of proteins. Disturbances in the luminal homeostasis result in the accumulation of unfolded proteins, thereby eliciting a stress response, the so-called unfolded protein response (UPR). Accumulated proteins are either deleterious due to the functional loss of the respective protein and/or due to their deposition as intra- or extracellular protein aggregates. A variety of metabolic diseases are known to date, which are associated with the dysfunction of components of the chaperone machinery. In this review, we will delineate the impact of ERdj proteins in controlling protein synthesis and translocation under physiological and under stress conditions. A second aspect of this review is dedicated to the role of ERdj proteins in the ER-associated degradation pathway, by which unfolded or misfolded proteins are discharged from the ER. We will refer to some of the most prominent diseases known to be based on the dysfunction of ERdj proteins.

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“…Furthermore, we verified the cellular interactions between GABA A receptors and three ubiquitin E3 ligases that we identified (LTN1, UBR5, and TRIM21) (Figure 4A). Mammalian ubiquitin E3 ligases play a central role in the ubiquitination and targeting of their client proteins to the cellular clearance pathway (45)(46)(47). Therefore, these E3 ligases are promising candidates to direct GABA A receptors to the proteasome for degradation.…”

Section: Verification Of the Role Of Selected Gaba A Receptors Proteo...mentioning

confidence: 99%

Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors

Wang

2022

Preprint

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Gamma-aminobutyric acid type A (GABAA) receptors, the primary inhibitory neurotransmitter-gated ion channels in the mammalian central nervous system, inhibit neuronal firing to preserve balanced neuronal activity. Maintenance of GABAA receptor protein homeostasis (proteostasis) in the cell utilizing its interacting proteins is essential for the function of GABAA receptors. However, how the proteostasis network orchestrates GABAA receptor biogenesis in the endoplasmic reticulum (ER) is not well understood. To address this question systematically, we employed a proteomics-based approach to identify the interactomes of GABAA receptors by carrying out a quantitative immunoprecipitation-tandem mass spectrometry (IP-MS/MS) analysis utilizing stable isotope labeling by amino acids in cell culture (SILAC). To enhance the coverage and reliability of the identified proteins, we performed comparative proteomics by using both wild type alpha1 subunit and a misfolding-prone alpha1 subunit carrying the A322D variant as the bait proteins. The wild type alpha1 interactome contains 125 proteins, the alpha1(A322D) interactome contains 105 proteins, and 54 proteins overlap within two interactomes. Bioinformatics analysis identified potential GABAA receptor proteostasis network components, including chaperones, folding enzymes, trafficking factors, and degradation factors. Further, their potential involvement is modelled in the cellular folding, degradation and trafficking pathways for GABAA receptors. In addition, we verified endogenous interactions between alpha1 subunit and their selected interactors by carrying out co-immunoprecipitation assay in mouse brain homogenates. This study paves the way for understanding the molecular mechanisms as well as fine-tuning of GABAA receptor proteostasis to ameliorate related neurological diseases such as epilepsy.

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Order through destruction: how ER‐associated protein degradation contributes to organelle homeostasis

Cited by 88 publications

References 133 publications

Vimentin intermediate filaments organize organellar architecture in response to ER stress

Vimentin intermediate filaments organize organellar architecture in response to ER stress

Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum

Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors

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Order through destruction: how ER‐associated protein degradation contributes to organelle homeostasis

Cited by 88 publications

References 133 publications

Vimentin intermediate filaments organize organellar architecture in response to ER stress

Vimentin intermediate filaments organize organellar architecture in response to ER stress

Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum

Quantitative interactome proteomics identifies proteostasis network for GABAAreceptors

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Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors