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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.


Distinct endoplasmic reticulum-associated degradation (ERAD) pathways. Three main ERAD pathways in yeast are classified based on substrates and the components that are involved in their degradation. ERAD-L degrades membrane integrated or soluble proteins with misfolded domains in the ER lumen, marked with (L). All depicted constituents of the Hrd1-complex are required for the efficient degradation of these substrates. ERAD-M degrades membrane integrated proteins with misfolded regions in their transmembrane domain(s), marked with (M). Proteins of this class are degraded via the Hrd1-complex but do not require Usa1p and Der1p for efficient degradation. ERAD-C degrades membrane integrated proteins with misfolded domains in the cytoplasm, marked with (C). These proteins are degraded via the Doa10-complex. All ERAD pathways require cytosolic Cdc48p for substrate retrotranslocation and extraction from the ER membrane. The substrate is ubiquitinated by the E3 ligases during or after retrotranslocation and is targeted to the proteasome (PRT) for degradation. Cdc48p and the 19S cap of the proteasome have structural and functional similarities. The classification for the different ERAD pathways also exists in mammalian cells albeit it is less stringent. RING = RING domain of the E3 ligases that are shown in red. The associated constituents of the individual complexes are shown in grey. Ub = ubiquitin. See text for details.
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cells-03-00824-f001: Distinct endoplasmic reticulum-associated degradation (ERAD) pathways. Three main ERAD pathways in yeast are classified based on substrates and the components that are involved in their degradation. ERAD-L degrades membrane integrated or soluble proteins with misfolded domains in the ER lumen, marked with (L). All depicted constituents of the Hrd1-complex are required for the efficient degradation of these substrates. ERAD-M degrades membrane integrated proteins with misfolded regions in their transmembrane domain(s), marked with (M). Proteins of this class are degraded via the Hrd1-complex but do not require Usa1p and Der1p for efficient degradation. ERAD-C degrades membrane integrated proteins with misfolded domains in the cytoplasm, marked with (C). These proteins are degraded via the Doa10-complex. All ERAD pathways require cytosolic Cdc48p for substrate retrotranslocation and extraction from the ER membrane. The substrate is ubiquitinated by the E3 ligases during or after retrotranslocation and is targeted to the proteasome (PRT) for degradation. Cdc48p and the 19S cap of the proteasome have structural and functional similarities. The classification for the different ERAD pathways also exists in mammalian cells albeit it is less stringent. RING = RING domain of the E3 ligases that are shown in red. The associated constituents of the individual complexes are shown in grey. Ub = ubiquitin. See text for details.

Mentions: It has been observed that the location of misfolded domain(s) on ERAD substrates is decisive for which ERAD machinery complex is used for their subsequent degradation. Based on this, three major ERAD pathways have been defined (Figure 1). Membrane proteins with a misfolded cytosolic domain are generally targeted to the Doa10-complex, a pathway termed ERAD-C (C for cytosolic) [13]. Membrane proteins with a misfolded luminal domain are generally targeted to the Hrd1-complex, a pathway termed ERAD-L (L for luminal) [13]. The same pathway degrades soluble misfolded proteins of the ER lumen. Finally, membrane proteins with a misfolded region in their transmembrane domain(s) are also targeted to the Hrd1-complex. However, in this case, fewer associated components are required for the degradation of these substrates; this pathway was termed ERAD-M (M for membrane) [14,15,16]. The correlation between substrate class and “choice” of pathway is strongest in yeast but is also found in mammalian cells, albeit to a lesser extent.


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

Lemus L, Goder V - Cells (2014)

Distinct endoplasmic reticulum-associated degradation (ERAD) pathways. Three main ERAD pathways in yeast are classified based on substrates and the components that are involved in their degradation. ERAD-L degrades membrane integrated or soluble proteins with misfolded domains in the ER lumen, marked with (L). All depicted constituents of the Hrd1-complex are required for the efficient degradation of these substrates. ERAD-M degrades membrane integrated proteins with misfolded regions in their transmembrane domain(s), marked with (M). Proteins of this class are degraded via the Hrd1-complex but do not require Usa1p and Der1p for efficient degradation. ERAD-C degrades membrane integrated proteins with misfolded domains in the cytoplasm, marked with (C). These proteins are degraded via the Doa10-complex. All ERAD pathways require cytosolic Cdc48p for substrate retrotranslocation and extraction from the ER membrane. The substrate is ubiquitinated by the E3 ligases during or after retrotranslocation and is targeted to the proteasome (PRT) for degradation. Cdc48p and the 19S cap of the proteasome have structural and functional similarities. The classification for the different ERAD pathways also exists in mammalian cells albeit it is less stringent. RING = RING domain of the E3 ligases that are shown in red. The associated constituents of the individual complexes are shown in grey. Ub = ubiquitin. See text for details.
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Related In: Results  -  Collection

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cells-03-00824-f001: Distinct endoplasmic reticulum-associated degradation (ERAD) pathways. Three main ERAD pathways in yeast are classified based on substrates and the components that are involved in their degradation. ERAD-L degrades membrane integrated or soluble proteins with misfolded domains in the ER lumen, marked with (L). All depicted constituents of the Hrd1-complex are required for the efficient degradation of these substrates. ERAD-M degrades membrane integrated proteins with misfolded regions in their transmembrane domain(s), marked with (M). Proteins of this class are degraded via the Hrd1-complex but do not require Usa1p and Der1p for efficient degradation. ERAD-C degrades membrane integrated proteins with misfolded domains in the cytoplasm, marked with (C). These proteins are degraded via the Doa10-complex. All ERAD pathways require cytosolic Cdc48p for substrate retrotranslocation and extraction from the ER membrane. The substrate is ubiquitinated by the E3 ligases during or after retrotranslocation and is targeted to the proteasome (PRT) for degradation. Cdc48p and the 19S cap of the proteasome have structural and functional similarities. The classification for the different ERAD pathways also exists in mammalian cells albeit it is less stringent. RING = RING domain of the E3 ligases that are shown in red. The associated constituents of the individual complexes are shown in grey. Ub = ubiquitin. See text for details.
Mentions: It has been observed that the location of misfolded domain(s) on ERAD substrates is decisive for which ERAD machinery complex is used for their subsequent degradation. Based on this, three major ERAD pathways have been defined (Figure 1). Membrane proteins with a misfolded cytosolic domain are generally targeted to the Doa10-complex, a pathway termed ERAD-C (C for cytosolic) [13]. Membrane proteins with a misfolded luminal domain are generally targeted to the Hrd1-complex, a pathway termed ERAD-L (L for luminal) [13]. The same pathway degrades soluble misfolded proteins of the ER lumen. Finally, membrane proteins with a misfolded region in their transmembrane domain(s) are also targeted to the Hrd1-complex. However, in this case, fewer associated components are required for the degradation of these substrates; this pathway was termed ERAD-M (M for membrane) [14,15,16]. The correlation between substrate class and “choice” of pathway is strongest in yeast but is also found in mammalian cells, albeit to a lesser extent.

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.