Title: A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice.
Authors: Quach, Christine; Song, Ying; Guo, Hongrui; Li, Shun; Maazi, Hadi; Fung, Marshall; Sands, Nathaniel; O'Connell, Douglas; Restrepo-Vassalli, Sara; Chai, Billy; Nemecio, Dali; Punj, Vasu; Akbari, Omid; Idos, Gregory E; Mumenthaler, Shannon M; Wu, Nancy; Martin, Sue Ellen; Hagiya, Ashley; Hicks, James; Cui, Hengmin; Liang, Chengyu
Published In Nat Commun, (2019 12 12)
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 UVRAGFS. 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.
PubMed ID: 31831743
MeSH Terms: Animals; Autophagy/genetics*; Carcinogenesis/genetics*; Carcinogenesis/pathology; Cell Proliferation; Centrosome; Colitis; Colonic Neoplasms/pathology; Colorectal Neoplasms/genetics; Female; Frameshift Mutation; Inflammasomes; Inflammation/genetics*; Lipopolysaccharides/adverse effects; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation*; NLR Family, Pyrin Domain-Containing 3 Protein; Sepsis; Starvation; Toll-Like Receptor 4/metabolism; Tumor Suppressor Proteins/genetics*