Christine Quach, Ying Song, Hongrui Guo, Shun Li, Hadi Maazi, Marshall Fung, Nathaniel Sands, Douglas O'Connell, Sara Restrepo-Vassalli, Billy Chai, Dali Nemecio, Vasu Punj, Omid Akbari, Gregory E Idos, Shannon M Mumenthaler, Nancy Wu, Sue Ellen Martin, Ashley Hagiya, James Hicks, Hengmin Cui, Chengyu Liang
Nature communications 2019 Dec 12Aberrant 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.
Christine Quach, Ying Song, Hongrui Guo, Shun Li, Hadi Maazi, Marshall Fung, Nathaniel Sands, Douglas O'Connell, Sara Restrepo-Vassalli, Billy Chai, Dali Nemecio, Vasu Punj, Omid Akbari, Gregory E Idos, Shannon M Mumenthaler, Nancy Wu, Sue Ellen Martin, Ashley Hagiya, James Hicks, Hengmin Cui, Chengyu Liang. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nature communications. 2019 Dec 12;10(1):5681
PMID: 31831743
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