A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice

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 and Chengyu Liang ()
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Christine Quach: University of Southern California
Ying Song: University of Southern California
Hongrui Guo: University of Southern California
Shun Li: University of Southern California
Hadi Maazi: University of Southern California
Marshall Fung: University of Southern California
Nathaniel Sands: University of Southern California
Douglas O’Connell: University of Southern California
Sara Restrepo-Vassalli: University of Southern California
Billy Chai: University of Southern California
Dali Nemecio: University of Southern California
Vasu Punj: University of Southern California
Omid Akbari: University of Southern California
Gregory E. Idos: University of Southern California
Shannon M. Mumenthaler: University of Southern California
Nancy Wu: University of Southern California
Sue Ellen Martin: University of Southern California
Ashley Hagiya: University of Southern California
James Hicks: University of Southern California
Hengmin Cui: Sichuan Agriculture University
Chengyu Liang: University of Southern California

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13475-w

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