UVRAG, the ultraviolet radiation resistance-associated gene, is a key regulator of mammalian macroautophagy/autophagy. It interacts with BECN1, PIK3C3, and RUBCN, playing a vital role in autophagy-related pathways. Dysregulation of autophagy, in which UVRAG is involved, has implications in inflammation, tumor cell proliferation, and other biological processes. Genetic models, such as mouse models with UVRAG mutations, are valuable for studying its functions [1,3].

A frameshift (FS) mutation in UVRAG in colorectal cancer (CRC) with microsatellite instability (MSI) truncates the protein. This truncated form acts in a dominant-negative manner, counteracting the tumor-suppressor functions of wild-type UVRAG in autophagy, centrosome stability, and DNA repair, promoting tumorigenesis, epithelial-to-mesenchymal transition, and metastasis [4]. In Alzheimer's disease, UVRAG downregulation impairs autophagy flux, leading to p62 accumulation, RIPK1 self-oligomerization, and activation of the RIPK1/RIPK3/MLKL cascade, resulting in TNF-α-dependent neuronal necroptosis. Overexpression of UVRAG inhibits this neuronal necroptosis [2].

In summary, UVRAG is essential for autophagy regulation. Mouse models with UVRAG mutations have revealed its role in diseases like CRC and Alzheimer's disease. In CRC, its mutation can switch its function from a tumor suppressor to an oncogene, while in Alzheimer's disease, its downregulation contributes to neuronal necroptosis. Understanding UVRAG's functions through these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Feng, Xing, Jia, Yanyan, Zhang, Yuyu, Qiu, Xingfeng, Zhang, Zhiyong. 2019. Ubiquitination of UVRAG by SMURF1 promotes autophagosome maturation and inhibits hepatocellular carcinoma growth. In Autophagy, 15, 1130-1149. doi:10.1080/15548627.2019.1570063. https://pubmed.ncbi.nlm.nih.gov/30686098/

2. Xu, Chong, Wu, Jialin, Wu, Yiqun, Chen, Xijing, Sima, Jian. 2021. TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG. In Theranostics, 11, 9452-9469. doi:10.7150/thno.62376. https://pubmed.ncbi.nlm.nih.gov/34646380/

3. Song, Ying, Quach, Christine, Liang, Chengyu. 2020. UVRAG in autophagy, inflammation, and cancer. In Autophagy, 16, 387-388. doi:10.1080/15548627.2019.1709768. https://pubmed.ncbi.nlm.nih.gov/31905312/

4. He, Shanshan, Liang, Chengyu. . Frameshift mutation of UVRAG: Switching a tumor suppressor to an oncogene in colorectal cancer. In Autophagy, 11, 1939-40. doi:10.1080/15548627.2015.1086523. https://pubmed.ncbi.nlm.nih.gov/26327192/