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Lhs1 dependent ERAD is determined by transmembrane domain context.

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|September 13, 2023
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Summary

The endoplasmic reticulum chaperone Lhs1 targets specific unglycosylated transmembrane proteins with two transmembrane domains (TMDs) for degradation. Lhs1-dependent degradation also involves the Hrd1 ubiquitin ligase, offering insights into substrate identification.

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endoplasmic reticulummolecular chaperonesproteasomestransmembrane proteins

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Area of Science:

  • Cell Biology
  • Protein Folding
  • Endoplasmic Reticulum Quality Control

Background:

  • Transmembrane proteins require specific folding and integration into the ER membrane.
  • Folding occurs in distinct cellular compartments (ER lumen, lipid bilayer, cytosol) with unique chaperones.
  • ER-associated degradation (ERAD) machinery identifies misfolded proteins.

Purpose of the Study:

  • To clarify the substrate specificity of the ER lumenal chaperone Lhs1 in ERAD.
  • To identify features dictating Lhs1-dependent degradation.
  • To understand Lhs1's role in protein quality control.

Main Methods:

  • Investigated Lhs1's role in the degradation of epithelial sodium channel (ENaC) subunits.
  • Analyzed features of Lhs1-dependent ERAD substrates.
  • Examined the impact of disrupting ENaC subunit assembly on degradation.
  • Assessed the overlap between Lhs1 and Hrd1 ubiquitin ligase pathways.

Main Results:

  • Lhs1-dependent substrates are unglycosylated and possess two transmembrane domains (TMDs).
  • Orphaned or unassembled TMDs characterize Lhs1 substrates.
  • Disrupting ENaC trimer assembly triggers Lhs1-dependent degradation of the entire complex.
  • Lhs1 acts on a subset of ERAD substrates also requiring the Hrd1 ubiquitin ligase.

Conclusions:

  • Lhs1 targets specific transmembrane proteins, characterized by unglycosylation and multiple TMDs.
  • Inter-subunit interactions influence Lhs1-mediated degradation.
  • Lhs1 and Hrd1 collaborate in specific ERAD pathways.
  • Identified key features for Lhs1 substrate recognition, potentially applicable to mammalian homolog GRP170.