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Regulation of Endoplasmic Reticulum-Associated Protein Degradation (ERAD) by Ubiquitin.

Lemus L, Goder V - Cells (2014)

Bottom Line: Quality control of protein folding inside the endoplasmic reticulum (ER) includes chaperone-mediated assistance in folding and the selective targeting of terminally misfolded species to a pathway called ER-associated protein degradation, or simply ERAD.Recently it became evident, however, that the poly-ubiquitin chains (PUCs) on ERAD substrates are often subject to extensive remodeling, or processing, at several stages during ERAD.This review recapitulates the current knowledge and recent findings about PUC processing on ERAD substrates and ubiquitination of ERAD machinery components and discusses their functional consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Seville, Av. Reina Mercedes 6, 41012 Seville, Spain.

ABSTRACT
Quality control of protein folding inside the endoplasmic reticulum (ER) includes chaperone-mediated assistance in folding and the selective targeting of terminally misfolded species to a pathway called ER-associated protein degradation, or simply ERAD. Once selected for ERAD, substrates will be transported (back) into the cytosol, a step called retrotranslocation. Although still ill defined, retrotranslocation likely involves a protein conducting channel that is in part formed by specific membrane-embedded E3 ubiquitin ligases. Early during retrotranslocation, reversible self-ubiquitination of these ligases is thought to aid in initiation of substrate transfer across the membrane. Once being at least partially exposed to the cytosol, substrates will become ubiquitinated on the cytosolic side of the ER membrane by the same E3 ubiquitin ligases. Ubiquitin on substrates was originally thought to be a permanent modification that (1) promotes late steps of retrotranslocation by recruiting the energy-providing ATPase Cdc48p/p97 via binding to its associated adaptor proteins and that (2) serves to target substrates to the proteasome. Recently it became evident, however, that the poly-ubiquitin chains (PUCs) on ERAD substrates are often subject to extensive remodeling, or processing, at several stages during ERAD. This review recapitulates the current knowledge and recent findings about PUC processing on ERAD substrates and ubiquitination of ERAD machinery components and discusses their functional consequences.

No MeSH data available.


Related in: MedlinePlus

Models for ubiquitination and deubiquitination of ERAD machinery components as a mechanism to regulate ERAD. (A) Regulation through degradation. In the mammalian system, ubiquitination of the ERAD component Ubl4A by the E3 ligase gp78 leads to the degradation of the associated shuttling chaperone Bag6, thereby reducing efficient substrate targeting to the proteasome. Ubl4A ubiquitination is reversed by the DUB Usp13. A similar mechanism involves the self-ubiquitination of Hrd1p in yeast in absence of Hrd3p and Usa1p, leading to effective degradation of the E3 ligase. No DUB is currently known in this system. See text for details. (B) Regulation through conformational changes. Binding of a substrate to Hrd1p in the ER lumen induces oligomerization and self-ubiquitination of the E3 ligase (step 1). Subsequently, ATP hydrolysis by bound Cdc48p would result in conformational changes in the ATPase, which will consequently result in conformational changes in Hrd1p oligomers. This, in turn, would push the substrate through a postulated channel formed by Hrd1p oligomers (together with associated components like Der1p) until it is partially exposed to the cytosol (step 2). See text for details.
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cells-03-00824-f005: Models for ubiquitination and deubiquitination of ERAD machinery components as a mechanism to regulate ERAD. (A) Regulation through degradation. In the mammalian system, ubiquitination of the ERAD component Ubl4A by the E3 ligase gp78 leads to the degradation of the associated shuttling chaperone Bag6, thereby reducing efficient substrate targeting to the proteasome. Ubl4A ubiquitination is reversed by the DUB Usp13. A similar mechanism involves the self-ubiquitination of Hrd1p in yeast in absence of Hrd3p and Usa1p, leading to effective degradation of the E3 ligase. No DUB is currently known in this system. See text for details. (B) Regulation through conformational changes. Binding of a substrate to Hrd1p in the ER lumen induces oligomerization and self-ubiquitination of the E3 ligase (step 1). Subsequently, ATP hydrolysis by bound Cdc48p would result in conformational changes in the ATPase, which will consequently result in conformational changes in Hrd1p oligomers. This, in turn, would push the substrate through a postulated channel formed by Hrd1p oligomers (together with associated components like Der1p) until it is partially exposed to the cytosol (step 2). See text for details.

Mentions: Several recent studies started to reveal that ubiquitination and deubiquitination also occurs on ERAD machinery components [29,107,113]. Self-ubiquitination and subsequent degradation as one mode of regulation of cellular ubiquitination machineries has been known for some time, reviewed in [114]. One such example relevant for ERAD is the regulation of the E3 ubiquitin ligase Hrd1p in yeast. Hrd1p undergoes self-ubiquitination and degradation in dependence on its binding partners Hrd3p (Sel1) and Usa1p (Usa1) [115,116,117] (Figure 5A). Such a scenario might also involve additional regulating elements like DUBs. In support of this, the DUB YOD1 was recently shown to affect the turnover of a non-ubiquitinated ERAD substrate in mammalian cells, implying that this DUB might act on ERAD machinery components [113]. Since YOD1 is also known to act on PUCs on substrates, these results suggest that certain DUBs can process ubiquitins or PUCs on substrates and on ERAD machinery components. Another example relevant for ERAD links the failure of DUB activity and the following degradation of an aberrantly ubiquitinated machinery component with downregulation of ERAD in mammalian cells [29]. The authors of the study investigated the regulation of the Bag6 chaperone system which keeps aggregation-prone retrotranslocated and membrane-extracted ERAD substrates in a soluble yet unfolded state for targeting to the proteasome [118]. Bag6 is bound to the ER membrane by multiple interactions, but binds specifically to gp78, a membrane-embedded E3 ligase similar to Hrd1p in yeast [119]. Strikingly, Usp13, a DUB associated to p97, affected the stability of the Bag6 complex. Failure of Usp13 activity lead to the polyubiquitantion of the Bag6 complex component Ubl4A by gp78 [29]. As a result, Bag6 is degraded, leading to downregulation of ERAD (Figure 5A).


Regulation of Endoplasmic Reticulum-Associated Protein Degradation (ERAD) by Ubiquitin.

Lemus L, Goder V - Cells (2014)

Models for ubiquitination and deubiquitination of ERAD machinery components as a mechanism to regulate ERAD. (A) Regulation through degradation. In the mammalian system, ubiquitination of the ERAD component Ubl4A by the E3 ligase gp78 leads to the degradation of the associated shuttling chaperone Bag6, thereby reducing efficient substrate targeting to the proteasome. Ubl4A ubiquitination is reversed by the DUB Usp13. A similar mechanism involves the self-ubiquitination of Hrd1p in yeast in absence of Hrd3p and Usa1p, leading to effective degradation of the E3 ligase. No DUB is currently known in this system. See text for details. (B) Regulation through conformational changes. Binding of a substrate to Hrd1p in the ER lumen induces oligomerization and self-ubiquitination of the E3 ligase (step 1). Subsequently, ATP hydrolysis by bound Cdc48p would result in conformational changes in the ATPase, which will consequently result in conformational changes in Hrd1p oligomers. This, in turn, would push the substrate through a postulated channel formed by Hrd1p oligomers (together with associated components like Der1p) until it is partially exposed to the cytosol (step 2). See text for details.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4197631&req=5

cells-03-00824-f005: Models for ubiquitination and deubiquitination of ERAD machinery components as a mechanism to regulate ERAD. (A) Regulation through degradation. In the mammalian system, ubiquitination of the ERAD component Ubl4A by the E3 ligase gp78 leads to the degradation of the associated shuttling chaperone Bag6, thereby reducing efficient substrate targeting to the proteasome. Ubl4A ubiquitination is reversed by the DUB Usp13. A similar mechanism involves the self-ubiquitination of Hrd1p in yeast in absence of Hrd3p and Usa1p, leading to effective degradation of the E3 ligase. No DUB is currently known in this system. See text for details. (B) Regulation through conformational changes. Binding of a substrate to Hrd1p in the ER lumen induces oligomerization and self-ubiquitination of the E3 ligase (step 1). Subsequently, ATP hydrolysis by bound Cdc48p would result in conformational changes in the ATPase, which will consequently result in conformational changes in Hrd1p oligomers. This, in turn, would push the substrate through a postulated channel formed by Hrd1p oligomers (together with associated components like Der1p) until it is partially exposed to the cytosol (step 2). See text for details.
Mentions: Several recent studies started to reveal that ubiquitination and deubiquitination also occurs on ERAD machinery components [29,107,113]. Self-ubiquitination and subsequent degradation as one mode of regulation of cellular ubiquitination machineries has been known for some time, reviewed in [114]. One such example relevant for ERAD is the regulation of the E3 ubiquitin ligase Hrd1p in yeast. Hrd1p undergoes self-ubiquitination and degradation in dependence on its binding partners Hrd3p (Sel1) and Usa1p (Usa1) [115,116,117] (Figure 5A). Such a scenario might also involve additional regulating elements like DUBs. In support of this, the DUB YOD1 was recently shown to affect the turnover of a non-ubiquitinated ERAD substrate in mammalian cells, implying that this DUB might act on ERAD machinery components [113]. Since YOD1 is also known to act on PUCs on substrates, these results suggest that certain DUBs can process ubiquitins or PUCs on substrates and on ERAD machinery components. Another example relevant for ERAD links the failure of DUB activity and the following degradation of an aberrantly ubiquitinated machinery component with downregulation of ERAD in mammalian cells [29]. The authors of the study investigated the regulation of the Bag6 chaperone system which keeps aggregation-prone retrotranslocated and membrane-extracted ERAD substrates in a soluble yet unfolded state for targeting to the proteasome [118]. Bag6 is bound to the ER membrane by multiple interactions, but binds specifically to gp78, a membrane-embedded E3 ligase similar to Hrd1p in yeast [119]. Strikingly, Usp13, a DUB associated to p97, affected the stability of the Bag6 complex. Failure of Usp13 activity lead to the polyubiquitantion of the Bag6 complex component Ubl4A by gp78 [29]. As a result, Bag6 is degraded, leading to downregulation of ERAD (Figure 5A).

Bottom Line: Quality control of protein folding inside the endoplasmic reticulum (ER) includes chaperone-mediated assistance in folding and the selective targeting of terminally misfolded species to a pathway called ER-associated protein degradation, or simply ERAD.Recently it became evident, however, that the poly-ubiquitin chains (PUCs) on ERAD substrates are often subject to extensive remodeling, or processing, at several stages during ERAD.This review recapitulates the current knowledge and recent findings about PUC processing on ERAD substrates and ubiquitination of ERAD machinery components and discusses their functional consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Seville, Av. Reina Mercedes 6, 41012 Seville, Spain.

ABSTRACT
Quality control of protein folding inside the endoplasmic reticulum (ER) includes chaperone-mediated assistance in folding and the selective targeting of terminally misfolded species to a pathway called ER-associated protein degradation, or simply ERAD. Once selected for ERAD, substrates will be transported (back) into the cytosol, a step called retrotranslocation. Although still ill defined, retrotranslocation likely involves a protein conducting channel that is in part formed by specific membrane-embedded E3 ubiquitin ligases. Early during retrotranslocation, reversible self-ubiquitination of these ligases is thought to aid in initiation of substrate transfer across the membrane. Once being at least partially exposed to the cytosol, substrates will become ubiquitinated on the cytosolic side of the ER membrane by the same E3 ubiquitin ligases. Ubiquitin on substrates was originally thought to be a permanent modification that (1) promotes late steps of retrotranslocation by recruiting the energy-providing ATPase Cdc48p/p97 via binding to its associated adaptor proteins and that (2) serves to target substrates to the proteasome. Recently it became evident, however, that the poly-ubiquitin chains (PUCs) on ERAD substrates are often subject to extensive remodeling, or processing, at several stages during ERAD. This review recapitulates the current knowledge and recent findings about PUC processing on ERAD substrates and ubiquitination of ERAD machinery components and discusses their functional consequences.

No MeSH data available.


Related in: MedlinePlus