<scp>EGAD</scp>
            ! There is an
            <scp>ERAD</scp>
            doppelganger in the Golgi

Fonseca, Daniel; Carvalho, Pedro

doi:10.15252/embj.2019102679

Cited by 9 publications

(12 citation statements)

References 11 publications

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“…It has been shown that a specific set of proteasomes and their protein partners are associated with the ER, Golgi, and plasma membrane 48 , 49 . Based on the results obtained in Figures 3 and 4 , we decided to determine the co-fractionation of the proteasome with the ER and Golgi in the iodixanol gradient fractionation.…”

Section: Resultsmentioning

confidence: 99%

“…The potential proteasome 26S and 30S in Figure 3 and the location of the second peak of Golgi in Figure 5 A suggest that a large part of capped proteasome complexes (26S and 30S) are co-fractionated with the Golgi apparatus. It has recently been shown that the 26S proteasome complex is associated with the Golgi apparatus as part of Golgi Apparatus-Related Degradation, or GARD, which plays a critical role in the late secretory pathway in normal conditions 48 and various secretion-related pathologies 53 . Expectedly, the ERAD protein p97 54 co-fractionated with proteasome complexes present in enriched ER/Golgi compartments, while P47, pan 14-3-3, and Gankyrin were dominantly found in early fractions (fractions 1-6), which correspond to lighter forms of proteasome complexes.…”

Section: Resultsmentioning

confidence: 99%

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Proteasome Complexes and Their Heterogeneity in Colorectal, Breast and Pancreatic Cancers

et al. 2021

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Targeting the ubiquitin-proteasome system (UPS)-in particular, the proteasome complex-has emerged as an attractive novel cancer therapy. While several proteasome inhibitors have been successfully approved by the Food and Drug Administration for the treatment of hematological malignancies, the clinical efficacy of these inhibitors is unexpectedly lower in the treatment of solid tumors due to the functional and structural heterogeneity of proteasomes in solid tumors. There are ongoing trials to examine the effectiveness of compound and novel proteasome inhibitors that can target solid tumors either alone or in combination with conventional chemotherapeutic agents. The modest therapeutic efficacy of proteasome inhibitors such as bortezomib in solid malignancies demands further research to clarify the exact effects of these proteasome inhibitors on different proteasomes present in cancer cells. The structural, cellular localization and functional analysis of the proteasome complexes in solid tumors originated from different tissues provides new insights into the diversity of proteasomes' responses to inhibitors. In this study, we used an optimized iodixanol gradient ultracentrifugation to purify a native form of proteasome complexes with their intact associated protein partners enriched within distinct cellular compartments. It is therefore possible to isolate proteasome subcomplexes with far greater resolution than sucrose or glycerol fractionations. We have identified differences in the catalytic activities, subcellular distribution, and inhibitor sensitivity of cytoplasmic proteasomes isolated from human colon, breast, and pancreatic cancer cell lines. Our developed techniques and generated results will serve as a valuable guideline for investigators developing a new generation of proteasome inhibitors as an effective targeted therapy for solid tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Proteasome Complexes and Their Heterogeneity in Colorectal, Breast and Pancreatic Cancers

et al. 2021

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“…Nonetheless, other E3 ligases exist that show different specificity for substrates [64]. Similar to ERAD, an endosome and Golgi-related stress-responsive associated degradation pathway (EGAD) exists in the Golgi [4]. EGAD is implicated in several processes including changes in the size, subcellular localization and organization of the Golgi, thus impacting on cell fate and cellular pathways.…”

Section: Maintenance Of Early Secretory Pathway Homeostasis and Immentioning

confidence: 99%

“…ER-dependent protein quality control imposes a collaboration between protein synthesis and productive folding, ER-associated degradation (ERAD) [2] and ER homeostasis control (unfolded protein response; UPR) [3]. In addition, Golgi-dependent quality control mechanisms are necessary to monitor polypeptides maturation and post-translational modifications [4]. For instance, modifications such as N-linked glycosylation, which is critical for protein recognition and integral maturation, is initiated in the ER and completed in the Golgi.…”

Section: Introductionmentioning

confidence: 99%

Control of Protein Homeostasis in the Early Secretory Pathway: Current Status and Challenges

Sicari

Igbaria

Chevet

2019

Cells

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: Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors involved in such process, both endoplasmic reticulum (ER) and the Golgi complex play prominent roles in protein synthesis, biogenesis and secretion. ER and Golgi functions ensure that only properly folded proteins are allowed to flow through the secretory pathway while improperly folded proteins have to be eliminated to not impinge on cellular functions. Thus, complex quality control and degradation machineries are crucial to prevent the toxic accumulation of improperly folded proteins. However, in some instances, improperly folded proteins can escape the quality control systems thereby contributing to several human diseases. Herein, we summarize how the early secretory pathways copes with the accumulation of improperly folded proteins, and how insufficient handling can cause the development of several human diseases. Finally, we detail the genetic and pharmacologic approaches that could be used as potential therapeutic tools to treat these diseases.

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“…Dsc3 contains a Ubl domain, and shares some similarities to the transmembrane and ubiquitin-like (Ubl) domain containing protein 1/2 (TMUB1/2). Ubx3 has a C-terminal UBX domain that can bind to Cdc48 18 , and is related to the FAS-associated factor 2 (FAF2/UBXD8).Overall, the subunit architecture of the Dsc complex resembles ubiquitin ligase complexes that function in ER associated degradation (ERAD) [19][20][21][22] .The Dsc complex can ubiquitinate ectopically expressed, non-native proteins at Golgi and endosomes, 16,23,24 . The Vld1-Dsc complex ubiquitinates native vacuolar membrane proteins (mainly lysosomal transmembrane transporters) 25,26 .…”

mentioning

confidence: 99%

The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

Weyer,

Schwabl,

Tang

et al. 2024

Preprint

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The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex, particularly the rhomboid pseudo-protease subunit, Dsc2, assesses the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be K63 polyubiquitinated for ESCRT dependent vacuolar degradation or K48 polyubiquitinated for endosome and Golgi associated proteasomal degradation (EGAD). Other Dsc substrates are exclusively extracted by Cdc48 for EGAD. The accumulation of Dsc substrates entails a specific increase in glycerophospholipids with shorter and asymmetric fatty acyl chains. Hence, the Dsc complex mediates the selective degradation of orphaned proteins at the sorting center of cells, which prevents their spreading across other organelles and thus preserves cellular membrane protein and lipid composition.

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EGAD ! There is an ERAD doppelganger in the Golgi

Cited by 9 publications

References 11 publications

Proteasome Complexes and Their Heterogeneity in Colorectal, Breast and Pancreatic Cancers

Proteasome Complexes and Their Heterogeneity in Colorectal, Breast and Pancreatic Cancers

Control of Protein Homeostasis in the Early Secretory Pathway: Current Status and Challenges

The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

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