CALCOCO1 is a soluble reticulophagy receptor

Area of Science:

• Cell Biology
• Autophagy Research
• Organelle Homeostasis

Background:

• The endoplasmic reticulum (ER) is a vital organelle regulating cellular processes.
• ER stress triggers ER expansion, necessitating degradation pathways like reticulophagy for size restoration.
• Reticulophagy receptors mediate the targeted degradation of ER components via autophagy.

Purpose of the Study:

• To identify novel soluble receptors involved in reticulophagy.
• To elucidate the mechanism by which CALCOCO1 mediates ER degradation during stress.

Main Methods:

• Utilized cell culture models to study ER stress responses.
• Investigated protein-protein interactions involving CALCOCO1, VAPA, VAPB, and Atg8-family proteins.
• Assessed the impact of CALCOCO1 depletion on ER degradation during proteotoxic and starvation stress.

Main Results:

• Identified CALCOCO1 as a soluble reticulophagy receptor crucial for tubular ER degradation.
• Demonstrated that CALCOCO1 binds ER membrane proteins VAPA/VAPB via a FFAT-like motif.
• Showed CALCOCO1 recruits autophagy machinery through co-dependent LIR and UIR motifs, interacting with Atg8-family proteins.
• Confirmed that CALCOCO1 depletion impairs ER degradation under stress conditions.

Conclusions:

• CALCOCO1 acts as a critical soluble receptor in reticulophagy, targeting specific ER portions for degradation.
• The interaction of CALCOCO1 with both ER membrane proteins and autophagy components is essential for efficient ER quality control.
• This study expands our understanding of the molecular mechanisms governing ER homeostasis during cellular stress.