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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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The Unfolded Protein Response01:37

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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Direct and essential function for Hrd3 in ER-associated degradation.

Nidhi Vashistha1, Sonya E Neal1, Amanjot Singh1

  • 1Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.

Proceedings of the National Academy of Sciences of the United States of America
|May 13, 2016
PubMed
Summary

Hrd3 is essential for the HMG-CoA reductase degradation (HRD) pathway, playing a critical role in endoplasmic reticulum-associated degradation (ERAD) beyond stabilizing Hrd1. This finding clarifies Hrd3

Keywords:
ERADHRD pathwayHRD3quality controlubiquitin

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Area of Science:

  • Cellular Biology
  • Protein Degradation Pathways
  • Endoplasmic Reticulum Quality Control

Background:

  • The HMG-CoA reductase degradation (HRD) pathway facilitates endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins.
  • Hrd1, an E3 ligase, targets ERAD substrates for ubiquitination and degradation.
  • Hrd1 functions within a complex with Hrd3, an ER membrane protein crucial for HRD-dependent degradation.

Purpose of the Study:

  • To investigate the independent functions of Hrd3 in ERAD beyond its role in Hrd1 stabilization.
  • To resolve the extent to which Hrd3 contributes to ERAD independently of Hrd1 stability.

Main Methods:

  • Utilized a novel approach based on studies of Usa1 in Hrd1 degradation.
  • Evaluated Hrd3 functions in ERAD using this new methodology.

Main Results:

  • Demonstrated that Hrd3 possesses a direct and critical role in ERAD, independent of Hrd1 stabilization.
  • This direct function of Hrd3 is as significant as Hrd1's role within the native HRD complex.
  • Hrd3's requirement is for Hrd1's E3 activity, not for substrate or E2 recruitment.

Conclusions:

  • Hrd3 plays an indispensable role in ERAD in living cells.
  • While Hrd1 can exhibit some function independently of Hrd3, Hrd3's contribution is essential for the overall process.