A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice
Identifieur interne : 000A52 ( Pmc/Checkpoint ); précédent : 000A51; suivant : 000A53A 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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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></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31831743</idno><idno type="pmc">6908726</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908726</idno><idno type="RBID">PMC:6908726</idno><idno type="doi">10.1038/s41467-019-13475-w</idno><date when="2019">2019</date><idno 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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></author><author><name sortKey="Guo, Hongrui" sort="Guo, Hongrui" uniqKey="Guo H" first="Hongrui" last="Guo">Hongrui Guo</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="Aff2"><institution-wrap><institution-id 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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. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Levine, B" uniqKey="Levine B">B Levine</name></author><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G Kroemer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mizushima, N" uniqKey="Mizushima N">N Mizushima</name></author><author><name sortKey="Levine, B" uniqKey="Levine B">B Levine</name></author><author><name sortKey="Cuervo, Am" uniqKey="Cuervo A">AM Cuervo</name></author><author><name sortKey="Klionsky, Dj" uniqKey="Klionsky D">DJ Klionsky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singh, R" uniqKey="Singh R">R Singh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nakahira, K" uniqKey="Nakahira K">K 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31831743</article-id><article-id pub-id-type="pmc">6908726</article-id><article-id pub-id-type="publisher-id">13475</article-id><article-id pub-id-type="doi">10.1038/s41467-019-13475-w</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>A truncating mutation in the autophagy gene <italic>UVRAG</italic> drives inflammation and tumorigenesis in mice</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4802-8013</contrib-id><name><surname>Quach</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Song</surname><given-names>Ying</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Guo</surname><given-names>Hongrui</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Shun</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-8979-3769</contrib-id><name><surname>Maazi</surname><given-names>Hadi</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fung</surname><given-names>Marshall</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sands</surname><given-names>Nathaniel</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4530-6113</contrib-id><name><surname>O’Connell</surname><given-names>Douglas</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Restrepo-Vassalli</surname><given-names>Sara</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Chai</surname><given-names>Billy</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-2263-3904</contrib-id><name><surname>Nemecio</surname><given-names>Dali</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Punj</surname><given-names>Vasu</given-names></name><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Akbari</surname><given-names>Omid</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Idos</surname><given-names>Gregory E.</given-names></name><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-2687-3769</contrib-id><name><surname>Mumenthaler</surname><given-names>Shannon M.</given-names></name><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Nancy</given-names></name><xref ref-type="aff" rid="Aff8">8</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5556-387X</contrib-id><name><surname>Martin</surname><given-names>Sue Ellen</given-names></name><xref ref-type="aff" rid="Aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Hagiya</surname><given-names>Ashley</given-names></name><xref ref-type="aff" rid="Aff9">9</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5353-4338</contrib-id><name><surname>Hicks</surname><given-names>James</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Cui</surname><given-names>Hengmin</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Liang</surname><given-names>Chengyu</given-names></name><address><email>chengyu.liang@med.usc.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><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</aff><aff id="Aff2"><label>2</label><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</aff><aff id="Aff3"><label>3</label><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</aff><aff id="Aff4"><label>4</label><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</aff><aff id="Aff5"><label>5</label><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</aff><aff id="Aff6"><label>6</label><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</aff><aff id="Aff7"><label>7</label><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</aff><aff id="Aff8"><label>8</label><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</aff><aff id="Aff9"><label>9</label><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</aff></contrib-group><pub-date pub-type="epub"><day>12</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>12</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>5681</elocation-id><history><date date-type="received"><day>13</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>5</day><month>11</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><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. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.</p></abstract><abstract id="Abs2" abstract-type="web-summary"><p id="Par2">UVRAG is involved in autophagy, which loses its tumour suppressor functions when in its truncated form in cancers. Here, the authors use a mouse model that inducibly express this truncated protein and show impaired autophagy, enhanced inflammation and β-catenin stabilisation, which promotes spontaneous tumorigenesis.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Biochemistry</kwd><kwd>Mechanisms of disease</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000066</institution-id><institution>U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)</institution></institution-wrap></funding-source><award-id>R01ES029092</award-id><principal-award-recipient><name><surname>Liang</surname><given-names>Chengyu</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100011541</institution-id><institution>U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics)</institution></institution-wrap></funding-source><award-id>R01 CA 140964</award-id><principal-award-recipient><name><surname>Liang</surname><given-names>Chengyu</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Quach, Christine" sort="Quach, Christine" uniqKey="Quach C" first="Christine" last="Quach">Christine Quach</name></region><name sortKey="Akbari, Omid" sort="Akbari, Omid" uniqKey="Akbari O" first="Omid" last="Akbari">Omid Akbari</name><name sortKey="Chai, Billy" sort="Chai, Billy" uniqKey="Chai B" first="Billy" last="Chai">Billy Chai</name><name sortKey="Fung, Marshall" sort="Fung, Marshall" uniqKey="Fung M" first="Marshall" last="Fung">Marshall Fung</name><name sortKey="Guo, Hongrui" sort="Guo, Hongrui" uniqKey="Guo H" 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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