ATL3, a cargo receptor for reticulophagy

Area of Science:

• Cell Biology
• Molecular Biology
• Neuroscience

Background:

• The endoplasmic reticulum (ER) is a vital organelle for cellular homeostasis, requiring regulated turnover.
• Selective macroautophagy of the ER, termed reticulophagy, maintains ER balance, but its mechanisms and significance are poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanisms and physiological relevance of reticulophagy.
• To identify novel receptors involved in the selective degradation of the ER.

Main Methods:

• Investigated the role of atlastin GTPase 3 (ATL3) in reticulophagy.
• Utilized co-immunoprecipitation assays to study ATL3 interactions with GABARAP proteins.
• Examined the impact of HSANI-associated ATL3 mutations on GABARAP binding and reticulophagy function.

Main Results:

• Identified ATL3, previously known for ER fusion, as a key receptor for reticulophagy.
• Demonstrated that ATL3 specifically interacts with GABARAP proteins (Atg8-family) to mediate ER selective autophagy.
• Showed that HSANI-associated mutations in ATL3 disrupt GABARAP binding and impair reticulophagy.

Conclusions:

• ATL3 plays a critical role as a receptor in reticulophagy, linking ER turnover to cellular homeostasis.
• The findings uncover a novel function for ATL3 beyond ER fusion.
• Dysfunctional reticulophagy due to ATL3 mutations may contribute to neurodegenerative diseases like HSANI, highlighting its physiological relevance.