RETREG3/FAM134C phosphorylation by CSNK2 regulates reticulophagy during starvation

Area of Science:

• Cellular Biology
• Molecular Biology
• Metabolism

Background:

• Autophagy is a cellular process essential for survival, particularly during starvation.
• While autophagy activation is understood, substrate selection mechanisms remain unclear.
• Selective autophagy, like reticulophagy, targets specific organelles for degradation.

Purpose of the Study:

• To elucidate the signaling pathway regulating selective autophagic removal of the endoplasmic reticulum (reticulophagy) during starvation.
• To investigate the role of the MTORC1-RETREG3 pathway in reticulophagy.
• To explore the physiological relevance of this pathway in vivo.

Main Methods:

• Investigated the effect of MTORC1 inhibition on reticulophagy receptor RETREG3/FAM134C.
• Assessed the role of CSNK2/CK2 in RETREG3 phosphorylation.
• Utilized in vivo models to study RETREG3 depletion and its impact on liver lipid metabolism.
• Developed a novel in vivo approach for studying selective autophagy.

Main Results:

• MTORC1 inhibition activates the reticulophagy receptor RETREG3/FAM134C by preventing its phosphorylation by CSNK2/CK2.
• RETREG3 depletion impairs MTORC1-dependent regulation of lipid metabolism in the liver.
• A novel in vivo method for studying selective autophagy was established.

Conclusions:

• A novel signaling pathway involving MTORC1 and RETREG3 mediates selective endoplasmic reticulum degradation during starvation.
• This pathway plays a significant role in regulating hepatic lipid metabolism.
• The developed in vivo approach may facilitate the discovery of new roles for selective autophagy.