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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.


A model for poly-ubiquitin chain (PUC) processing as a mechanism for coupling ER protein quality control with ERAD. Membrane proteins with exposed cytosolic domains are ubiquitinated by E3 ligases. Due to topological confinement of membrane proteins and membrane integrated E3 ligases to the same bilayer, ubiquitination might occur frequently, even on correctly folded proteins. DUBs can remove ubiquitins, favoring ER export of correctly folded species. Reoccurring ubiquitination due to prolonged ER retention as a result of misfolding (in the cytosol or ER lumen) will favor the assembly of PUCs to induce targeting to the proteasome, thereby favoring ERAD. A similar mechanism might occur for soluble proteins prior to their post-translational translocation across the ER membrane, a pathway called prERAD. See text for details. E3 = E3 ligase. DUB = deubiquitinase. Filled green circles: ubiquitin.
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cells-03-00824-f002: A model for poly-ubiquitin chain (PUC) processing as a mechanism for coupling ER protein quality control with ERAD. Membrane proteins with exposed cytosolic domains are ubiquitinated by E3 ligases. Due to topological confinement of membrane proteins and membrane integrated E3 ligases to the same bilayer, ubiquitination might occur frequently, even on correctly folded proteins. DUBs can remove ubiquitins, favoring ER export of correctly folded species. Reoccurring ubiquitination due to prolonged ER retention as a result of misfolding (in the cytosol or ER lumen) will favor the assembly of PUCs to induce targeting to the proteasome, thereby favoring ERAD. A similar mechanism might occur for soluble proteins prior to their post-translational translocation across the ER membrane, a pathway called prERAD. See text for details. E3 = E3 ligase. DUB = deubiquitinase. Filled green circles: ubiquitin.

Mentions: ER membrane proteins are often directly accessible to the cytosolic ubiquitination machinery through their cytosolic domains and ubiquitination of these domains could result in a direct signal for ERAD. Recently, however, ubiquitination of cytosolic domains of ER membrane proteins was proposed to have a function prior to their degradation and would instead be involved in their quality control [34]. In this particular case, the authors investigated the traffic of mammalian lipoprotein receptor-related protein-6 (LRP6) [35]. LRP6 is a type I membrane protein with a large luminal domain and a shorter cytoplasmic tail. It is constitutively palmitoylated at one or possibly two juxtamembranous cysteines, and is normally targeted to the plasma membrane for its function in Wnt signaling. Abrogation of palmitoylation by mutating the critical cysteine residues resulted in mono-ubiquitination on a proximal lysine residue [35]. However, mono-ubiquitination did not trigger ERAD but resulted in protein retention inside the ER. The authors suggested that the observed initial mono-ubiquitination would be a first and critical step in the quality control of particular membrane proteins and would prevent the protein from being prematurely exported from the ER. In addition to that, mono-ubiquitinated substrate would also allow recruitment of yet-to-be defined cytosolic quality control components, potentially including chaperones and folding sensors [34]. Prolonged retention of the protein in the ER will lead to the extension of mono-ubiquitin by E3 ligases and to the formation of PUCs. Initially this could be reversed by DUBs but eventually, in case that protein folding attempts repeatedly fail, PUCs would form which are recognized by the ERAD system (Figure 2). Clearly, the model is still very hypothetical and needs more experimental backup for validation. For instance, it is still unclear which E3 ligases or DUBs are involved in modifying LRP6. Despite all these uncertainties, the model is appealing with the concept that E3 ligases and DUBs are involved in modifying PUCs on cytosolic domains of ER membrane proteins in a similar manner and with similar consequences like ER luminal UDP-glucose:glycoprotein glucosyltransferase (GT) and Glucosidase II, which are involved in modifying N-glycans on proteins for quality control in the ER lumen [36].


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

Lemus L, Goder V - Cells (2014)

A model for poly-ubiquitin chain (PUC) processing as a mechanism for coupling ER protein quality control with ERAD. Membrane proteins with exposed cytosolic domains are ubiquitinated by E3 ligases. Due to topological confinement of membrane proteins and membrane integrated E3 ligases to the same bilayer, ubiquitination might occur frequently, even on correctly folded proteins. DUBs can remove ubiquitins, favoring ER export of correctly folded species. Reoccurring ubiquitination due to prolonged ER retention as a result of misfolding (in the cytosol or ER lumen) will favor the assembly of PUCs to induce targeting to the proteasome, thereby favoring ERAD. A similar mechanism might occur for soluble proteins prior to their post-translational translocation across the ER membrane, a pathway called prERAD. See text for details. E3 = E3 ligase. DUB = deubiquitinase. Filled green circles: ubiquitin.
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Related In: Results  -  Collection

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cells-03-00824-f002: A model for poly-ubiquitin chain (PUC) processing as a mechanism for coupling ER protein quality control with ERAD. Membrane proteins with exposed cytosolic domains are ubiquitinated by E3 ligases. Due to topological confinement of membrane proteins and membrane integrated E3 ligases to the same bilayer, ubiquitination might occur frequently, even on correctly folded proteins. DUBs can remove ubiquitins, favoring ER export of correctly folded species. Reoccurring ubiquitination due to prolonged ER retention as a result of misfolding (in the cytosol or ER lumen) will favor the assembly of PUCs to induce targeting to the proteasome, thereby favoring ERAD. A similar mechanism might occur for soluble proteins prior to their post-translational translocation across the ER membrane, a pathway called prERAD. See text for details. E3 = E3 ligase. DUB = deubiquitinase. Filled green circles: ubiquitin.
Mentions: ER membrane proteins are often directly accessible to the cytosolic ubiquitination machinery through their cytosolic domains and ubiquitination of these domains could result in a direct signal for ERAD. Recently, however, ubiquitination of cytosolic domains of ER membrane proteins was proposed to have a function prior to their degradation and would instead be involved in their quality control [34]. In this particular case, the authors investigated the traffic of mammalian lipoprotein receptor-related protein-6 (LRP6) [35]. LRP6 is a type I membrane protein with a large luminal domain and a shorter cytoplasmic tail. It is constitutively palmitoylated at one or possibly two juxtamembranous cysteines, and is normally targeted to the plasma membrane for its function in Wnt signaling. Abrogation of palmitoylation by mutating the critical cysteine residues resulted in mono-ubiquitination on a proximal lysine residue [35]. However, mono-ubiquitination did not trigger ERAD but resulted in protein retention inside the ER. The authors suggested that the observed initial mono-ubiquitination would be a first and critical step in the quality control of particular membrane proteins and would prevent the protein from being prematurely exported from the ER. In addition to that, mono-ubiquitinated substrate would also allow recruitment of yet-to-be defined cytosolic quality control components, potentially including chaperones and folding sensors [34]. Prolonged retention of the protein in the ER will lead to the extension of mono-ubiquitin by E3 ligases and to the formation of PUCs. Initially this could be reversed by DUBs but eventually, in case that protein folding attempts repeatedly fail, PUCs would form which are recognized by the ERAD system (Figure 2). Clearly, the model is still very hypothetical and needs more experimental backup for validation. For instance, it is still unclear which E3 ligases or DUBs are involved in modifying LRP6. Despite all these uncertainties, the model is appealing with the concept that E3 ligases and DUBs are involved in modifying PUCs on cytosolic domains of ER membrane proteins in a similar manner and with similar consequences like ER luminal UDP-glucose:glycoprotein glucosyltransferase (GT) and Glucosidase II, which are involved in modifying N-glycans on proteins for quality control in the ER lumen [36].

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.