Chengyu Liang, M.D., Ph.D.
University of Southern California
NIEHS-funded researchers found that a mutation in the ultraviolet irradiation resistance-associated gene (UVRAG), a gene involved in cell regulation, can disrupt autophagy in mice, which results in increased inflammatory response and tumor development. Autophagy is the process of cleaning out damaged cells so the body can regenerate newer, healthier cells. Abnormal autophagy is a known major risk factor for inflammatory diseases and cancer. This study provides the first genetic evidence connecting UVRAG suppression to autophagy regulation, inflammation, and cancer predisposition.
UVRAG knockout mice cannot survive beyond the embryo stage. To provide a new way to study the role of this gene, the researchers generated mice that expressed UVRAG with a frameshift mutation. This genetic mutation is caused by a deletion or insertion in a DNA sequence that shifts the way the sequence is read. These mice are normal in basal autophagy but deficient in autophagy induced by stimuli, such as starvation or immune activation.
The researchers induced sepsis or intestinal colitis and found that compared with normal mice, mice with the UVRAG mutation displayed increased inflammatory responses in both conditions. The mutated mice also had increased spontaneous tumor development. Increased tumors were linked to suppression of autophagy associated with aging, indicating that UVRAG could be one reason people are more susceptible to cancers as they get older.
Citation: Quach C, Song Y, Guo H, Li S, Maazi H, Fung M, Sands N, O'Connell D, Restrepo-Vassalli S, Chai B, Nemecio D, Punj V, Akbari O, Idos GE, Mumenthaler SM, Wu N, Martin SE, Hagiya A, Hicks J, Cui H, Liang C. 2019. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat Commun 10(1):5681.