UVRAG: orchestrating the initiation of reticulophagy

ABSTRACTReticulophagy 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: Autophagycargo receptorLC3/GABARAPreticulophagyUVRAGDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Additional informationFundingThe work was supported by the Fundamental Research Funds for the Central Universities [2042022dx0003]; National Key Research and Development Program of China [2021YFC2701600, 2021YFC2700700]; National Natural Science Foundation of China [32370806, 32070744]; Wuhan University [413100036]; National Key Research and Development Program of China [2021YFC2701602, 2021YFC2700702]; Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University [ZNJC202202].