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gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum.

Zhang T, Xu Y, Liu Y, Ye Y - Mol. Biol. Cell (2015)

Bottom Line: Eukaryotic cells eliminate misfolded proteins from the endoplasmic reticulum (ER) via a conserved process termed ER-associated degradation (ERAD).Instead, gp78 appears to act downstream of Hrd1 to promote ERAD via cooperation with the BAG6 chaperone complex.We conclude that the Hrd1 complex forms an essential retrotranslocation module that is evolutionarily conserved, but the mammalian ERAD system uses additional ubiquitin ligases to assist Hrd1 during retrotranslocation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.

No MeSH data available.


The functional relationship between gp78 and Hrd1. Hrd1 is the essential retrotranslocation regulator conserved in yeast and mammalian cells, whereas gp78 serves an assisting role downstream of Hrd1 and possibly another ubiquitin ligase in mammalian cells. gp78 may promote ERAD by maintaining the functionality of the BAG6 complex.
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Figure 7: The functional relationship between gp78 and Hrd1. Hrd1 is the essential retrotranslocation regulator conserved in yeast and mammalian cells, whereas gp78 serves an assisting role downstream of Hrd1 and possibly another ubiquitin ligase in mammalian cells. gp78 may promote ERAD by maintaining the functionality of the BAG6 complex.

Mentions: In summary, our study demonstrates that gp78 has an accessory function both downstream and in parallel with Hrd1 in ERAD. A plausible explanation for this observation is that gp78 may cooperate with both Hrd1 and another ubiquitin ligase, each of which forms a route to export ERAD substrates (Figure 7). This model is supported by genetic evidence that knockout of the hrd1 gene does not completely abolish either retrotranslocation or ubiquitination of MHC 1-147, and that knockdown of gp78 in Hrd1 CRISPR cells can lead to further stabilization of this substrate. We propose that the gp78 complex acts as an assisting module downstream of these ubiquitin ligases. The requirement for gp78 may be largely confined to substrates that are prone to aggregation, which necessitates the involvement of a downstream chaperone holdase such as BAG6. The proposed modular organization of the mammalian ERAD system resolves the long-standing discrepancy between the budding yeast and the mammalian ERAD systems, and indicates that de novo origination of additional accessory modules accounts for the complexity of the mammalian ERAD system.


gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum.

Zhang T, Xu Y, Liu Y, Ye Y - Mol. Biol. Cell (2015)

The functional relationship between gp78 and Hrd1. Hrd1 is the essential retrotranslocation regulator conserved in yeast and mammalian cells, whereas gp78 serves an assisting role downstream of Hrd1 and possibly another ubiquitin ligase in mammalian cells. gp78 may promote ERAD by maintaining the functionality of the BAG6 complex.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 7: The functional relationship between gp78 and Hrd1. Hrd1 is the essential retrotranslocation regulator conserved in yeast and mammalian cells, whereas gp78 serves an assisting role downstream of Hrd1 and possibly another ubiquitin ligase in mammalian cells. gp78 may promote ERAD by maintaining the functionality of the BAG6 complex.
Mentions: In summary, our study demonstrates that gp78 has an accessory function both downstream and in parallel with Hrd1 in ERAD. A plausible explanation for this observation is that gp78 may cooperate with both Hrd1 and another ubiquitin ligase, each of which forms a route to export ERAD substrates (Figure 7). This model is supported by genetic evidence that knockout of the hrd1 gene does not completely abolish either retrotranslocation or ubiquitination of MHC 1-147, and that knockdown of gp78 in Hrd1 CRISPR cells can lead to further stabilization of this substrate. We propose that the gp78 complex acts as an assisting module downstream of these ubiquitin ligases. The requirement for gp78 may be largely confined to substrates that are prone to aggregation, which necessitates the involvement of a downstream chaperone holdase such as BAG6. The proposed modular organization of the mammalian ERAD system resolves the long-standing discrepancy between the budding yeast and the mammalian ERAD systems, and indicates that de novo origination of additional accessory modules accounts for the complexity of the mammalian ERAD system.

Bottom Line: Eukaryotic cells eliminate misfolded proteins from the endoplasmic reticulum (ER) via a conserved process termed ER-associated degradation (ERAD).Instead, gp78 appears to act downstream of Hrd1 to promote ERAD via cooperation with the BAG6 chaperone complex.We conclude that the Hrd1 complex forms an essential retrotranslocation module that is evolutionarily conserved, but the mammalian ERAD system uses additional ubiquitin ligases to assist Hrd1 during retrotranslocation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.

No MeSH data available.