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

被引：49

作者：

Quach, Christine ^{[1
]}

Song, Ying ^{[1
]}

Guo, Hongrui ^{[1
,2
]}

Li, Shun ^{[1
,3
]}

Maazi, Hadi ^{[1
]}

Fung, Marshall ^{[1
]}

Sands, Nathaniel ^{[1
]}

O'Connell, Douglas ^{[1
]}

Restrepo-Vassalli, Sara ^{[4
]}

Chai, Billy ^{[1
]}

Nemecio, Dali ^{[1
]}

Punj, Vasu ^{[5
]}

Akbari, Omid ^{[1
]}

Idos, Gregory E. ^{[6
]}

Mumenthaler, Shannon M. ^{[7
]}

Wu, Nancy ^{[8
]}

Martin, Sue Ellen ^{[9
]}

Hagiya, Ashley ^{[9
]}

Hicks, James ^{[4
]}

Cui, Hengmin ^{[2
]}

Liang, Chengyu ^{[1
]}

机构：

[1] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA

[2] Sichuan Agr Univ, Coll Vet Med, Chengdu 611130, Sichuan, Peoples R China

[3] Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400044, Peoples R China

[4] Univ Southern Calif, USC Michelson Ctr Convergent Biosci, Bridge Inst, Los Angeles, CA 90089 USA

[5] Univ Southern Calif, Dept Med, Los Angeles, CA 90033 USA

[6] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA

[7] Univ Southern Calif, Lawrence J Ellison Inst Transformat Med, Los Angeles, CA 90033 USA

[8] Univ Southern Calif, Norris Comprehens Canc Ctr, Transgen Knockout Rodent Core Facil, Los Angeles, CA 90089 USA

[9] Univ Southern Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

PHOSPHATIDYLINOSITOL 3-KINASE COMPLEXES; NF-KAPPA-B; BETA-CATENIN; INTESTINAL INFLAMMATION; NLRP3; INFLAMMASOME; BECLIN; ACTIVATION; DISEASE; PROTEIN; CANCER;

D O I：

10.1038/s41467-019-13475-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 UVRAG(FS) in vivo, we generated mutant mice that inducibly express UVRAG(FS) (iUVRAG(FS)). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAG(FS) mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAG(FS) mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant beta-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.

引用

页数：19

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