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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 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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Competition between Der1 and ERAD-M substrates controls Hrd1 complex function.

Jennifer E Russ1, Brian G Peterson1, Sophia Taylor1

  • 1Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109.

Proceedings of the National Academy of Sciences of the United States of America
|December 2, 2025
PubMed
Summary
This summary is machine-generated.

Endoplasmic reticulum-associated degradation (ERAD) quality control relies on the Hrd1 ligase. New research identifies Hrd1 variants that impair integral membrane substrate degradation, revealing competition within the ERAD complex.

Keywords:
ERADdeep mutational scanningendoplasmic reticulum–associated degradationprotein degradationubiquitin proteasome system

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Protein Degradation

Background:

  • Endoplasmic reticulum-associated degradation (ERAD) is a crucial cellular quality control mechanism.
  • Hrd1 is an integral membrane ubiquitin ligase central to the conserved ERAD pathway.
  • ERAD targets misfolded proteins, including soluble and integral membrane types, for proteasomal degradation.

Purpose of the Study:

  • To identify specific Hrd1 residues critical for integral membrane substrate degradation.
  • To understand the mechanisms by which Hrd1 variants affect ERAD function.
  • To elucidate the interplay between different substrate types and ERAD complex components.

Main Methods:

  • Deep mutational scanning of the Hrd1 ligase.
  • In vivo assays to assess Hrd1 variant function.
  • Characterization of Hrd1-mediated degradation of integral membrane substrates.

Main Results:

  • Identified single-residue Hrd1 variants deficient in degrading integral membrane substrates.
  • Demonstrated competition between integral membrane substrates and other ERAD complex components for Hrd1 function.
  • Revealed that Hrd1 complex assembly dictates ERAD tuning.

Conclusions:

  • Hrd1 residues are exclusively involved in integral membrane substrate degradation.
  • Competition for the retrotranslocon cavity influences substrate degradation pathways.
  • Hrd1 complex assembly is a key regulator of ERAD pathway specificity and efficiency.