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

Nat Commun. 2019 Dec 12;10(1):5681. doi: 10.1038/s41467-019-13475-w.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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*


  • Inflammasomes
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Suppressor Proteins
  • UVRAG protein, mouse