UVRAG: orchestrating the initiation of reticulophagy

ABSTRACT

Reticulophagy is a selective autophagy of the endoplasmic reticulum (ER) mediated by cargo receptors. It plays a crucial role in ER quality control, yet the mechanisms that initiate reticulophagy remain poorly understood. Our study identified the multifunctional protein UVRAG (UV radiation resistance associated gene) as a novel regulator of reticulophagy. UVRAG interacts with sheet and tubular reticulophagy receptors, regulates the oligomerization of receptors and facilitates their interaction with LC3/GABARAP, critical for ER fragmentation and autophagosome targeting. Remarkably, we found that UVRAG’s function in reticulophagy initiation is independent of its traditional role in macroautophagy. Furthermore, UVRAG enhances the degradation of ER-associated mutant proteins linked to diseases like diabetes. Our findings offer insights into the mechanisms of reticulophagy initiation and highlight UVRAG’s therapeutic potential in ER-related diseases.

KEYWORDS:

• Autophagy
• cargo receptor
• LC3/GABARAP
• reticulophagy
• UVRAG

Disclosure statement

The authors have no conflicts of interest to disclose.

Additional information

Funding

This work was supported by the National Key Research and Development Program of China [2021YFC2701600, 2021YFC2701602, 2021YFC2700700, 2021YFC2700702], National Natural Science Foundation of China [32370806, 32070744]; Start Fund from Wuhan University [413100036]; Fundamental Research Funds for the Central Universities [2042022dx0003]; Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University [ZNJC202202].