1. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice.
- Author
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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, and Liang C
- Subjects
- Animals, Carcinogenesis pathology, Cell Proliferation, Centrosome, Colitis, Colonic Neoplasms pathology, Colorectal Neoplasms genetics, Female, Frameshift Mutation, Inflammasomes, Lipopolysaccharides adverse effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein, Sepsis, Starvation, Toll-Like Receptor 4 metabolism, Autophagy genetics, Carcinogenesis genetics, Inflammation genetics, Mutation, Tumor Suppressor Proteins genetics
- Abstract
Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAG
FS . To investigate the role of UVRAGFS in vivo, we generated mutant mice that inducibly express UVRAGFS (iUVRAGFS ). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAGFS mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAGFS mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.- Published
- 2019
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