Limited ER quality control for GPI-anchored proteins

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Endoplasmic reticulum (ER) quality control targets misfolded proteins for degradation via ER-associated degradation (ERAD).
• Misfolded GPI-anchored proteins (GPI-APs) are typically poor ERAD substrates, suggesting GPI anchors hinder ERAD.
• This leads to their degradation in the vacuole/lysosome.

Purpose of the Study:

• To investigate the degradation pathway of misfolded GPI-APs.
• To determine if GPI anchors obstruct ER-associated degradation (ERAD).
• To elucidate the mechanism behind the reduced ERAD susceptibility of misfolded GPI-APs.

Main Methods:

• Analysis of misfolded GPI-anchored protein Gas1* degradation in yeast.
• Utilizing Hrd1-dependent ERAD pathway.
• Investigating the role of GPI anchor remodeling in protein export.

Main Results:

• Misfolded Gas1* can be efficiently routed to Hrd1-dependent ERAD, confirming GPI anchors do not obstruct ERAD.
• GPI anchor remodeling, a process common to all GPI-APs, acts as a protein-independent ER export signal.
• This remodeling facilitates efficient ER export even for misfolded GPI-APs.

Conclusions:

• GPI anchor structure, not the anchor itself, influences ERAD substrate efficiency.
• GPI anchor remodeling overrides protein folding status, promoting ER export.
• ER quality control is inherently limited for the entire class of GPI-APs, impacting many clinically relevant proteins.