The K/HDEL receptor does not recycle but instead acts as a Golgi-gatekeeper

Area of Science:

• Cell Biology
• Molecular Biology
• Protein Trafficking

Background:

• The KDEL receptor (ERD2) is crucial for retaining proteins with a KDEL or HDEL C-terminal retrieval signal in the endoplasmic reticulum (ER).
• Previous models proposed rapid ER export as the primary mechanism for ERD2 function in receptor recycling.
• This study re-evaluates the ERD2 mechanism, challenging established models of ER protein retention.

Purpose of the Study:

• To investigate the precise mechanism by which the KDEL receptor (ERD2) retains ER-bound cargo.
• To determine whether ERD2 function relies on Golgi retention or rapid ER export.
• To elucidate the role of ERD2's C-terminus and COPI-mediated transport in its function.

Main Methods:

• Investigating ERD2's localization and function under conditions of C-terminal masking or mutation.
• Analyzing the impact of forced COPI-mediated retrograde transport on ERD2 activity.
• Assessing the effect of introducing alternative ER-to-Golgi export or cis-Golgi retention signals.

Main Results:

• ERD2 demonstrates Golgi retention, which is essential for its function, rather than fast ER export.
• Ligand-induced redistribution of ERD2 occurs only when its C-terminus is altered, disrupting the Golgi-to-ER transport signal.
• Disruption of COPI-mediated transport abolishes ERD2 function, while reintroducing specific signals can restore activity.

Conclusions:

• ERD2 acts as a Golgi gatekeeper, capturing KDEL-containing proteins and facilitating their retrograde transport back to the ER.
• The receptor's function is dependent on its retention within the Golgi apparatus.
• This Golgi-centric mechanism for KDEL receptor function is highly conserved across different species.