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Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
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Summary

The oligosaccharyltransferase (OST) complex, known for protein glycosylation, also aids in ER-associated degradation (ERAD). OST subunits interact with ERAD machinery, facilitating the removal of misfolded proteins.

Keywords:
ERADHRD1OSTendoplasmic reticulumretrotranslocation

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Area of Science:

  • Cell Biology
  • Protein Biochemistry
  • Molecular Biology

Background:

  • N-glycosylation is a crucial post-translational modification for most secreted and membrane proteins, catalyzed by the oligosaccharyltransferase (OST) complex in the endoplasmic reticulum (ER).
  • Proteins that fail quality control in the ER are targeted for degradation through ER-associated degradation (ERAD) or ER-phagy.
  • Previous studies suggested roles for OST subunits beyond their catalytic function in glycosylation.

Purpose of the Study:

  • To investigate the potential involvement of OST subunits in ER-associated degradation (ERAD) of misfolded proteins.
  • To elucidate the mechanism by which OST might participate in ERAD pathways.

Main Methods:

  • Stable isotope labeling by amino acids in cell culture (SILAC) proteomics to identify protein interactors.
  • Experimental manipulation of OST subunit expression (overexpression and knockdown).
  • Assays to monitor ERAD of various misfolded proteins (type I/II membrane proteins and soluble glycoproteins).
  • Molecular dynamics simulations.

Main Results:

  • OST subunits were identified as key interactors with misfolded ER proteins during proteasomal inhibition.
  • Modulating OST subunit levels (overexpression or knockdown) significantly impacted ERAD efficiency for both glycosylated and non-glycosylated proteins, independent of glycosylation levels.
  • OST subunits were found to interact with the E3 ligase HRD1 and facilitate the retrotranslocation step of ERAD.
  • Molecular dynamics simulations suggested that OST transmembrane domains may thin the ER membrane, potentially aiding retrotranslocation.

Conclusions:

  • The OST complex plays an unexpected, dual role in the ER, participating not only in N-glycosylation but also in the quality control and degradation of misfolded proteins via ERAD.
  • OST subunits are involved in the later stages of ERAD, interacting with HRD1 and potentially facilitating protein retrotranslocation through membrane distortion.