A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice
Identifieur interne : 000B29 ( Main/Exploration ); précédent : 000B28; suivant : 000B30A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice
Auteurs : Christine Quach [États-Unis] ; Ying Song [États-Unis] ; Hongrui Guo [États-Unis, République populaire de Chine] ; Shun Li [États-Unis, République populaire de Chine] ; Hadi Maazi [États-Unis] ; Marshall Fung [États-Unis] ; Nathaniel Sands [États-Unis] ; Douglas O Onnell [États-Unis] ; Sara Restrepo-Vassalli [États-Unis] ; Billy Chai [États-Unis] ; Dali Nemecio [États-Unis] ; Vasu Punj [États-Unis] ; Omid Akbari [États-Unis] ; Gregory E. Idos [États-Unis] ; Shannon M. Mumenthaler [États-Unis] ; Nancy Wu [États-Unis] ; Sue Ellen Martin [États-Unis] ; Ashley Hagiya [États-Unis] ; James Hicks [États-Unis] ; Hengmin Cui [République populaire de Chine] ; Chengyu Liang [États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2019.
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 (
Url:
DOI: 10.1038/s41467-019-13475-w
PubMed: 31831743
PubMed Central: 6908726
Affiliations:
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uniqKey="Quach C" first="Christine" last="Quach">Christine Quach</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Song, Ying" sort="Song, Ying" uniqKey="Song Y" first="Ying" last="Song">Ying Song</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id 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USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0185 3134</institution-id><institution-id institution-id-type="GRID">grid.80510.3c</institution-id><institution>College of Veterinary Medicine,</institution><institution>Sichuan Agriculture University,</institution></institution-wrap>Chengdu, 611130 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chengdu</wicri:regionArea></affiliation></author><author><name sortKey="Li, Shun" sort="Li, Shun" uniqKey="Li S" first="Shun" last="Li">Shun Li</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0154 0904</institution-id><institution-id institution-id-type="GRID">grid.190737.b</institution-id><institution>Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering,</institution><institution>Chongqing University,</institution></institution-wrap>Chongqing, 400044 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Maazi, Hadi" sort="Maazi, Hadi" uniqKey="Maazi H" first="Hadi" last="Maazi">Hadi Maazi</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Fung, Marshall" sort="Fung, Marshall" uniqKey="Fung M" first="Marshall" last="Fung">Marshall Fung</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Sands, Nathaniel" sort="Sands, Nathaniel" uniqKey="Sands N" first="Nathaniel" last="Sands">Nathaniel Sands</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="O Onnell, Douglas" sort="O Onnell, Douglas" uniqKey="O Onnell D" first="Douglas" last="O Onnell">Douglas O Onnell</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Restrepo Vassalli, Sara" sort="Restrepo Vassalli, Sara" uniqKey="Restrepo Vassalli S" first="Sara" last="Restrepo-Vassalli">Sara Restrepo-Vassalli</name><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>USC Michelson Center for Convergent Bioscience, Bridge Institute,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90089 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Chai, Billy" sort="Chai, Billy" uniqKey="Chai B" first="Billy" last="Chai">Billy Chai</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Nemecio, Dali" sort="Nemecio, Dali" uniqKey="Nemecio D" first="Dali" last="Nemecio">Dali Nemecio</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Punj, Vasu" sort="Punj, Vasu" uniqKey="Punj V" first="Vasu" last="Punj">Vasu Punj</name><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Akbari, Omid" sort="Akbari, Omid" uniqKey="Akbari O" first="Omid" last="Akbari">Omid Akbari</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Idos, Gregory E" sort="Idos, Gregory E" uniqKey="Idos G" first="Gregory E." last="Idos">Gregory E. Idos</name><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Norris Comprehensive Cancer Center,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90089 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Mumenthaler, Shannon M" sort="Mumenthaler, Shannon M" uniqKey="Mumenthaler S" first="Shannon M." last="Mumenthaler">Shannon M. Mumenthaler</name><affiliation wicri:level="2"><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Lawrence J. Ellison Institute for Transformative Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Wu, Nancy" sort="Wu, Nancy" uniqKey="Wu N" first="Nancy" last="Wu">Nancy Wu</name><affiliation wicri:level="2"><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Norris Comprehensive Cancer Center Transgenic/Knockout Rodent Core Facility,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90089 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Martin, Sue Ellen" sort="Martin, Sue Ellen" uniqKey="Martin S" first="Sue Ellen" last="Martin">Sue Ellen Martin</name><affiliation wicri:level="2"><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Pathology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Hagiya, Ashley" sort="Hagiya, Ashley" uniqKey="Hagiya A" first="Ashley" last="Hagiya">Ashley Hagiya</name><affiliation wicri:level="2"><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Pathology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Hicks, James" sort="Hicks, James" uniqKey="Hicks J" first="James" last="Hicks">James Hicks</name><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>USC Michelson Center for Convergent Bioscience, Bridge Institute,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90089 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Cui, Hengmin" sort="Cui, Hengmin" uniqKey="Cui H" first="Hengmin" last="Cui">Hengmin Cui</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0185 3134</institution-id><institution-id institution-id-type="GRID">grid.80510.3c</institution-id><institution>College of Veterinary Medicine,</institution><institution>Sichuan Agriculture University,</institution></institution-wrap>Chengdu, 611130 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chengdu</wicri:regionArea></affiliation></author><author><name sortKey="Liang, Chengyu" sort="Liang, Chengyu" uniqKey="Liang C" first="Chengyu" last="Liang">Chengyu Liang</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2156 6853</institution-id><institution-id institution-id-type="GRID">grid.42505.36</institution-id><institution>Department of Molecular Microbiology and Immunology, Keck School of Medicine,</institution><institution>University of Southern California,</institution></institution-wrap>Los Angeles, CA 90033 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Los Angeles</wicri:cityArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">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<sup>FS</sup>. To investigate the role of UVRAG<sup>FS</sup> in vivo, we generated mutant mice that inducibly express UVRAG<sup>FS</sup> (<italic>iUVRAG</italic><sup><italic>FS</italic></sup>). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. <italic>iUVRAG</italic><sup><italic>FS</italic></sup> mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, <italic>iUVRAG</italic><sup><italic>FS</italic></sup> mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. 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first="Hongrui" last="Guo">Hongrui Guo</name><name sortKey="Hagiya, Ashley" sort="Hagiya, Ashley" uniqKey="Hagiya A" first="Ashley" last="Hagiya">Ashley Hagiya</name><name sortKey="Hicks, James" sort="Hicks, James" uniqKey="Hicks J" first="James" last="Hicks">James Hicks</name><name sortKey="Idos, Gregory E" sort="Idos, Gregory E" uniqKey="Idos G" first="Gregory E." last="Idos">Gregory E. Idos</name><name sortKey="Li, Shun" sort="Li, Shun" uniqKey="Li S" first="Shun" last="Li">Shun Li</name><name sortKey="Liang, Chengyu" sort="Liang, Chengyu" uniqKey="Liang C" first="Chengyu" last="Liang">Chengyu Liang</name><name sortKey="Maazi, Hadi" sort="Maazi, Hadi" uniqKey="Maazi H" first="Hadi" last="Maazi">Hadi Maazi</name><name sortKey="Martin, Sue Ellen" sort="Martin, Sue Ellen" uniqKey="Martin S" first="Sue Ellen" last="Martin">Sue Ellen Martin</name><name sortKey="Mumenthaler, Shannon M" sort="Mumenthaler, Shannon M" uniqKey="Mumenthaler S" first="Shannon M." last="Mumenthaler">Shannon M. Mumenthaler</name><name sortKey="Nemecio, Dali" sort="Nemecio, Dali" uniqKey="Nemecio D" first="Dali" last="Nemecio">Dali Nemecio</name><name sortKey="O Onnell, Douglas" sort="O Onnell, Douglas" uniqKey="O Onnell D" first="Douglas" last="O Onnell">Douglas O Onnell</name><name sortKey="Punj, Vasu" sort="Punj, Vasu" uniqKey="Punj V" first="Vasu" last="Punj">Vasu Punj</name><name sortKey="Restrepo Vassalli, Sara" sort="Restrepo Vassalli, Sara" uniqKey="Restrepo Vassalli S" first="Sara" last="Restrepo-Vassalli">Sara Restrepo-Vassalli</name><name sortKey="Sands, Nathaniel" sort="Sands, Nathaniel" uniqKey="Sands N" first="Nathaniel" last="Sands">Nathaniel Sands</name><name sortKey="Song, Ying" sort="Song, Ying" uniqKey="Song Y" first="Ying" last="Song">Ying Song</name><name sortKey="Wu, Nancy" sort="Wu, Nancy" uniqKey="Wu N" first="Nancy" last="Wu">Nancy Wu</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Guo, Hongrui" sort="Guo, Hongrui" uniqKey="Guo H" first="Hongrui" last="Guo">Hongrui Guo</name></noRegion><name sortKey="Cui, Hengmin" sort="Cui, Hengmin" uniqKey="Cui H" first="Hengmin" last="Cui">Hengmin Cui</name><name sortKey="Li, Shun" sort="Li, Shun" uniqKey="Li S" first="Shun" last="Li">Shun Li</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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