Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.
Identifieur interne : 000088 ( Main/Exploration ); précédent : 000087; suivant : 000089Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.
Auteurs : Maria C Ferreira Dos Santos [États-Unis] ; Cole P. Anderson [États-Unis, Allemagne] ; Susanne Neschen [Allemagne] ; Kimberly B. Zumbrennen-Bullough [États-Unis] ; Steven J. Romney [États-Unis] ; Melanie Kahle-Stephan [Allemagne] ; Birgit Rathkolb [Allemagne] ; Valerie Gailus-Durner [Allemagne] ; Helmut Fuchs [Allemagne] ; Eckhard Wolf [Allemagne] ; Jan Rozman [Allemagne, République tchèque] ; Martin Hrabe De Angelis [Allemagne] ; Weiling Maggie Cai [Singapour] ; Malini Rajan [États-Unis] ; Jennifer Hu [États-Unis] ; Peter C. Dedon [États-Unis] ; Elizabeth A. Leibold [États-Unis]Source :
- Nature communications [ 2041-1723 ] ; 2020.
Descripteurs français
- KwdFr :
- ARN de transfert de la lysine (génétique), ARN de transfert de la lysine (métabolisme), Animaux (MeSH), Cellules à insuline (métabolisme), Fer (métabolisme), Ferrosulfoprotéines (métabolisme), Homéostasie (MeSH), Insuline (métabolisme), Insulinome (génétique), Insulinome (métabolisme), Intolérance au glucose (génétique), Lignée cellulaire tumorale (MeSH), Proinsuline (génétique), Proinsuline (métabolisme), Protéine-2 de régulation du fer (génétique), Protéine-2 de régulation du fer (métabolisme), Rats (MeSH), Réponse aux protéines mal repliées (génétique), Souris de lignée C57BL (MeSH), Souris knockout (MeSH), T-RNA methyltransferases (génétique), T-RNA methyltransferases (métabolisme), Tumeurs du pancréas (génétique), Tumeurs du pancréas (métabolisme).
- MESH :
- génétique : ARN de transfert de la lysine, Insulinome, Intolérance au glucose, Proinsuline, Protéine-2 de régulation du fer, Réponse aux protéines mal repliées, T-RNA methyltransferases, Tumeurs du pancréas.
- métabolisme : ARN de transfert de la lysine, Cellules à insuline, Fer, Ferrosulfoprotéines, Insuline, Insulinome, Proinsuline, Protéine-2 de régulation du fer, T-RNA methyltransferases, Tumeurs du pancréas.
- Animaux, Homéostasie, Lignée cellulaire tumorale, Rats, Souris de lignée C57BL, Souris knockout.
English descriptors
- KwdEn :
- Animals (MeSH), Cell Line, Tumor (MeSH), Glucose Intolerance (genetics), Homeostasis (MeSH), Insulin (metabolism), Insulin-Secreting Cells (metabolism), Insulinoma (genetics), Insulinoma (metabolism), Iron (metabolism), Iron Regulatory Protein 2 (genetics), Iron Regulatory Protein 2 (metabolism), Iron-Sulfur Proteins (metabolism), Mice, Inbred C57BL (MeSH), Mice, Knockout (MeSH), Pancreatic Neoplasms (genetics), Pancreatic Neoplasms (metabolism), Proinsulin (genetics), Proinsulin (metabolism), RNA, Transfer, Lys (genetics), RNA, Transfer, Lys (metabolism), Rats (MeSH), Unfolded Protein Response (genetics), tRNA Methyltransferases (genetics), tRNA Methyltransferases (metabolism).
- MESH :
- chemical , genetics : Iron Regulatory Protein 2, Proinsulin, RNA, Transfer, Lys, tRNA Methyltransferases.
- chemical , metabolism : Insulin, Iron, Iron Regulatory Protein 2, Iron-Sulfur Proteins, Proinsulin, RNA, Transfer, Lys, tRNA Methyltransferases.
- genetics : Glucose Intolerance, Insulinoma, Pancreatic Neoplasms, Unfolded Protein Response.
- metabolism : Insulin-Secreting Cells, Insulinoma, Pancreatic Neoplasms.
- Animals, Cell Line, Tumor, Homeostasis, Mice, Inbred C57BL, Mice, Knockout, Rats.
Abstract
Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t6A37 in tRNALysUUU to ms2t6A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms2t6A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2-/- β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.
DOI: 10.1038/s41467-019-14004-5
PubMed: 31941883
PubMed Central: PMC6962211
Affiliations:
- Allemagne, République tchèque, Singapour, États-Unis
- Bavière, District de Haute-Bavière
- Munich
- Université Louis-et-Maximilien de Munich, Université nationale de Singapour, Université technique de Munich
Links toward previous steps (curation, corpus...)
Le document en format XML
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last="Wolf">Eckhard Wolf</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></affiliation></author><author><name sortKey="Rozman, Jan" sort="Rozman, Jan" uniqKey="Rozman J" first="Jan" last="Rozman">Jan Rozman</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova, 595, 252 50 Vestec, Czech Republic.</nlm:affiliation><country xml:lang="fr">République tchèque</country><wicri:regionArea>Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova, 595, 252 50 Vestec</wicri:regionArea><wicri:noRegion>252 50 Vestec</wicri:noRegion></affiliation></author><author><name sortKey="De Angelis, Martin Hrabe" sort="De Angelis, Martin Hrabe" uniqKey="De Angelis M" first="Martin Hrabe" last="De Angelis">Martin Hrabe De Angelis</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising</wicri:regionArea><wicri:noRegion>85354, Freising</wicri:noRegion><orgName type="university">Université technique de Munich</orgName><placeName><settlement type="city">Munich</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region></placeName></affiliation></author><author><name sortKey="Cai, Weiling Maggie" sort="Cai, Weiling Maggie" uniqKey="Cai W" first="Weiling Maggie" last="Cai">Weiling Maggie Cai</name><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology, National University of Singapore, Singapore, Singapore, 119077.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation><affiliation><nlm:affiliation>Antimicrobial Resistance Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, Singapore, 138602.</nlm:affiliation><wicri:noCountry code="subField">138602</wicri:noCountry></affiliation><affiliation><nlm:affiliation>Agilent Technologies, 1 Yishun Ave 7, Singapore, Singapore, 768923.</nlm:affiliation><wicri:noCountry code="subField">768923</wicri:noCountry></affiliation></author><author><name sortKey="Rajan, Malini" sort="Rajan, Malini" uniqKey="Rajan M" first="Malini" last="Rajan">Malini Rajan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation></author><author><name sortKey="Hu, Jennifer" sort="Hu, Jennifer" uniqKey="Hu J" first="Jennifer" last="Hu">Jennifer Hu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139</wicri:regionArea><wicri:noRegion>02139</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Celgene Corporation, 1616 Eastlake Ave East, Seattle, WA, 98102, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Celgene Corporation, 1616 Eastlake Ave East, Seattle, WA, 98102</wicri:regionArea><wicri:noRegion>98102</wicri:noRegion></affiliation></author><author><name sortKey="Dedon, Peter C" sort="Dedon, Peter C" uniqKey="Dedon P" first="Peter C" last="Dedon">Peter C. Dedon</name><affiliation><nlm:affiliation>Antimicrobial Resistance Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, Singapore, 138602.</nlm:affiliation><wicri:noCountry code="subField">138602</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139</wicri:regionArea><wicri:noRegion>02139</wicri:noRegion></affiliation></author><author><name sortKey="Leibold, Elizabeth A" sort="Leibold, Elizabeth A" uniqKey="Leibold E" first="Elizabeth A" last="Leibold">Elizabeth A. Leibold</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:31941883</idno><idno type="pmid">31941883</idno><idno type="doi">10.1038/s41467-019-14004-5</idno><idno type="pmc">PMC6962211</idno><idno type="wicri:Area/Main/Corpus">000160</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000160</idno><idno type="wicri:Area/Main/Curation">000160</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000160</idno><idno type="wicri:Area/Main/Exploration">000160</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.</title><author><name sortKey="Santos, Maria C Ferreira Dos" sort="Santos, Maria C Ferreira Dos" uniqKey="Santos M" first="Maria C Ferreira Dos" last="Santos">Maria C Ferreira Dos Santos</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation></author><author><name sortKey="Anderson, Cole P" sort="Anderson, Cole P" uniqKey="Anderson C" first="Cole P" last="Anderson">Cole P. Anderson</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Landstuhl Regional Medical Center, 66849, Landstuhl, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Landstuhl Regional Medical Center, 66849, Landstuhl</wicri:regionArea><wicri:noRegion>66849, Landstuhl</wicri:noRegion><wicri:noRegion>66849, Landstuhl</wicri:noRegion><wicri:noRegion>Landstuhl</wicri:noRegion></affiliation></author><author><name sortKey="Neschen, Susanne" sort="Neschen, Susanne" uniqKey="Neschen S" first="Susanne" last="Neschen">Susanne Neschen</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Zumbrennen Bullough, Kimberly B" sort="Zumbrennen Bullough, Kimberly B" uniqKey="Zumbrennen Bullough K" first="Kimberly B" last="Zumbrennen-Bullough">Kimberly B. Zumbrennen-Bullough</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation></author><author><name sortKey="Romney, Steven J" sort="Romney, Steven J" uniqKey="Romney S" first="Steven J" last="Romney">Steven J. Romney</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Thermo Fisher Scientific, Waltham, MA, 02451, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Thermo Fisher Scientific, Waltham, MA, 02451</wicri:regionArea><wicri:noRegion>02451</wicri:noRegion></affiliation></author><author><name sortKey="Kahle Stephan, Melanie" sort="Kahle Stephan, Melanie" uniqKey="Kahle Stephan M" first="Melanie" last="Kahle-Stephan">Melanie Kahle-Stephan</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Medizinische Hochschule Brandenburg Theodor Fontane Institut für Sozialmedizin und Epidemiologie, 14770, Brandenburg an der Havel, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medizinische Hochschule Brandenburg Theodor Fontane Institut für Sozialmedizin und Epidemiologie, 14770, Brandenburg an der Havel</wicri:regionArea><wicri:noRegion>14770, Brandenburg an der Havel</wicri:noRegion><wicri:noRegion>14770, Brandenburg an der Havel</wicri:noRegion><wicri:noRegion>Brandenburg an der Havel</wicri:noRegion></affiliation></author><author><name sortKey="Rathkolb, Birgit" sort="Rathkolb, Birgit" uniqKey="Rathkolb B" first="Birgit" last="Rathkolb">Birgit Rathkolb</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></affiliation></author><author><name sortKey="Gailus Durner, Valerie" sort="Gailus Durner, Valerie" uniqKey="Gailus Durner V" first="Valerie" last="Gailus-Durner">Valerie Gailus-Durner</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Fuchs, Helmut" sort="Fuchs, Helmut" uniqKey="Fuchs H" first="Helmut" last="Fuchs">Helmut Fuchs</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Wolf, Eckhard" sort="Wolf, Eckhard" uniqKey="Wolf E" first="Eckhard" last="Wolf">Eckhard Wolf</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></affiliation></author><author><name sortKey="Rozman, Jan" sort="Rozman, Jan" uniqKey="Rozman J" first="Jan" last="Rozman">Jan Rozman</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova, 595, 252 50 Vestec, Czech Republic.</nlm:affiliation><country xml:lang="fr">République tchèque</country><wicri:regionArea>Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova, 595, 252 50 Vestec</wicri:regionArea><wicri:noRegion>252 50 Vestec</wicri:noRegion></affiliation></author><author><name sortKey="De Angelis, Martin Hrabe" sort="De Angelis, Martin Hrabe" uniqKey="De Angelis M" first="Martin Hrabe" last="De Angelis">Martin Hrabe De Angelis</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg</wicri:regionArea><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>85764, Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising</wicri:regionArea><wicri:noRegion>85354, Freising</wicri:noRegion><orgName type="university">Université technique de Munich</orgName><placeName><settlement type="city">Munich</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region></placeName></affiliation></author><author><name sortKey="Cai, Weiling Maggie" sort="Cai, Weiling Maggie" uniqKey="Cai W" first="Weiling Maggie" last="Cai">Weiling Maggie Cai</name><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology, National University of Singapore, Singapore, Singapore, 119077.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation><affiliation><nlm:affiliation>Antimicrobial Resistance Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, Singapore, 138602.</nlm:affiliation><wicri:noCountry code="subField">138602</wicri:noCountry></affiliation><affiliation><nlm:affiliation>Agilent Technologies, 1 Yishun Ave 7, Singapore, Singapore, 768923.</nlm:affiliation><wicri:noCountry code="subField">768923</wicri:noCountry></affiliation></author><author><name sortKey="Rajan, Malini" sort="Rajan, Malini" uniqKey="Rajan M" first="Malini" last="Rajan">Malini Rajan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation></author><author><name sortKey="Hu, Jennifer" sort="Hu, Jennifer" uniqKey="Hu J" first="Jennifer" last="Hu">Jennifer Hu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139</wicri:regionArea><wicri:noRegion>02139</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Celgene Corporation, 1616 Eastlake Ave East, Seattle, WA, 98102, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Celgene Corporation, 1616 Eastlake Ave East, Seattle, WA, 98102</wicri:regionArea><wicri:noRegion>98102</wicri:noRegion></affiliation></author><author><name sortKey="Dedon, Peter C" sort="Dedon, Peter C" uniqKey="Dedon P" first="Peter C" last="Dedon">Peter C. Dedon</name><affiliation><nlm:affiliation>Antimicrobial Resistance Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, Singapore, 138602.</nlm:affiliation><wicri:noCountry code="subField">138602</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139</wicri:regionArea><wicri:noRegion>02139</wicri:noRegion></affiliation></author><author><name sortKey="Leibold, Elizabeth A" sort="Leibold, Elizabeth A" uniqKey="Leibold E" first="Elizabeth A" last="Leibold">Elizabeth A. Leibold</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112</wicri:regionArea><wicri:noRegion>84112</wicri:noRegion></affiliation></author></analytic><series><title level="j">Nature communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Cell Line, Tumor (MeSH)</term><term>Glucose Intolerance (genetics)</term><term>Homeostasis (MeSH)</term><term>Insulin (metabolism)</term><term>Insulin-Secreting Cells (metabolism)</term><term>Insulinoma (genetics)</term><term>Insulinoma (metabolism)</term><term>Iron (metabolism)</term><term>Iron Regulatory Protein 2 (genetics)</term><term>Iron Regulatory Protein 2 (metabolism)</term><term>Iron-Sulfur Proteins (metabolism)</term><term>Mice, Inbred C57BL (MeSH)</term><term>Mice, Knockout (MeSH)</term><term>Pancreatic Neoplasms (genetics)</term><term>Pancreatic Neoplasms (metabolism)</term><term>Proinsulin (genetics)</term><term>Proinsulin (metabolism)</term><term>RNA, Transfer, Lys (genetics)</term><term>RNA, Transfer, Lys (metabolism)</term><term>Rats (MeSH)</term><term>Unfolded Protein Response (genetics)</term><term>tRNA Methyltransferases (genetics)</term><term>tRNA Methyltransferases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN de transfert de la lysine (génétique)</term><term>ARN de transfert de la lysine (métabolisme)</term><term>Animaux (MeSH)</term><term>Cellules à insuline (métabolisme)</term><term>Fer (métabolisme)</term><term>Ferrosulfoprotéines (métabolisme)</term><term>Homéostasie (MeSH)</term><term>Insuline (métabolisme)</term><term>Insulinome (génétique)</term><term>Insulinome (métabolisme)</term><term>Intolérance au glucose (génétique)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Proinsuline (génétique)</term><term>Proinsuline (métabolisme)</term><term>Protéine-2 de régulation du fer (génétique)</term><term>Protéine-2 de régulation du fer (métabolisme)</term><term>Rats (MeSH)</term><term>Réponse aux protéines mal repliées (génétique)</term><term>Souris de lignée C57BL (MeSH)</term><term>Souris knockout (MeSH)</term><term>T-RNA methyltransferases (génétique)</term><term>T-RNA methyltransferases (métabolisme)</term><term>Tumeurs du pancréas (génétique)</term><term>Tumeurs du pancréas (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Iron Regulatory Protein 2</term><term>Proinsulin</term><term>RNA, Transfer, Lys</term><term>tRNA Methyltransferases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Insulin</term><term>Iron</term><term>Iron Regulatory Protein 2</term><term>Iron-Sulfur Proteins</term><term>Proinsulin</term><term>RNA, Transfer, Lys</term><term>tRNA Methyltransferases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Glucose Intolerance</term><term>Insulinoma</term><term>Pancreatic Neoplasms</term><term>Unfolded Protein Response</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN de transfert de la lysine</term><term>Insulinome</term><term>Intolérance au glucose</term><term>Proinsuline</term><term>Protéine-2 de régulation du fer</term><term>Réponse aux protéines mal repliées</term><term>T-RNA methyltransferases</term><term>Tumeurs du pancréas</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Insulin-Secreting Cells</term><term>Insulinoma</term><term>Pancreatic Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN de transfert de la lysine</term><term>Cellules à insuline</term><term>Fer</term><term>Ferrosulfoprotéines</term><term>Insuline</term><term>Insulinome</term><term>Proinsuline</term><term>Protéine-2 de régulation du fer</term><term>T-RNA methyltransferases</term><term>Tumeurs du pancréas</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Homeostasis</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Rats</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Homéostasie</term><term>Lignée cellulaire tumorale</term><term>Rats</term><term>Souris de lignée C57BL</term><term>Souris knockout</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t<sup>6</sup>A37 in tRNA<sup>Lys</sup><sub>UUU</sub> to ms<sup>2</sup>t<sup>6</sup>A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms<sup>2</sup>t<sup>6</sup>A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2<sup>-/-</sup> β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31941883</PMID><DateCompleted><Year>2020</Year><Month>04</Month><Day>13</Day></DateCompleted><DateRevised><Year>2020</Year><Month>06</Month><Day>22</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2041-1723</ISSN><JournalIssue CitedMedium="Internet"><Volume>11</Volume><Issue>1</Issue><PubDate><Year>2020</Year><Month>01</Month><Day>15</Day></PubDate></JournalIssue><Title>Nature communications</Title><ISOAbbreviation>Nat Commun</ISOAbbreviation></Journal><ArticleTitle>Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.</ArticleTitle><Pagination><MedlinePgn>296</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/s41467-019-14004-5</ELocationID><Abstract><AbstractText>Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t<sup>6</sup>A37 in tRNA<sup>Lys</sup><sub>UUU</sub> to ms<sup>2</sup>t<sup>6</sup>A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms<sup>2</sup>t<sup>6</sup>A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2<sup>-/-</sup> β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Santos</LastName><ForeName>Maria C Ferreira Dos</ForeName><Initials>MCFD</Initials><Identifier Source="ORCID">0000-0003-0231-6538</Identifier><AffiliationInfo><Affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Anderson</LastName><ForeName>Cole P</ForeName><Initials>CP</Initials><AffiliationInfo><Affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Landstuhl Regional Medical Center, 66849, Landstuhl, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Neschen</LastName><ForeName>Susanne</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zumbrennen-Bullough</LastName><ForeName>Kimberly B</ForeName><Initials>KB</Initials><AffiliationInfo><Affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Romney</LastName><ForeName>Steven J</ForeName><Initials>SJ</Initials><AffiliationInfo><Affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Thermo Fisher Scientific, Waltham, MA, 02451, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kahle-Stephan</LastName><ForeName>Melanie</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Medizinische Hochschule Brandenburg Theodor Fontane Institut für Sozialmedizin und Epidemiologie, 14770, Brandenburg an der Havel, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rathkolb</LastName><ForeName>Birgit</ForeName><Initials>B</Initials><Identifier Source="ORCID">0000-0003-1239-0547</Identifier><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gailus-Durner</LastName><ForeName>Valerie</ForeName><Initials>V</Initials><Identifier Source="ORCID">0000-0002-6076-0111</Identifier><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fuchs</LastName><ForeName>Helmut</ForeName><Initials>H</Initials><Identifier Source="ORCID">0000-0002-5143-2677</Identifier><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wolf</LastName><ForeName>Eckhard</ForeName><Initials>E</Initials><Identifier Source="ORCID">0000-0002-0430-9510</Identifier><AffiliationInfo><Affiliation>Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rozman</LastName><ForeName>Jan</ForeName><Initials>J</Initials><Identifier Source="ORCID">0000-0002-8035-8904</Identifier><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prumyslova, 595, 252 50 Vestec, Czech Republic.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>de Angelis</LastName><ForeName>Martin Hrabe</ForeName><Initials>MH</Initials><Identifier Source="ORCID">0000-0002-7898-2353</Identifier><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cai</LastName><ForeName>Weiling Maggie</ForeName><Initials>WM</Initials><AffiliationInfo><Affiliation>Department of Microbiology, National University of Singapore, Singapore, Singapore, 119077.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Antimicrobial Resistance Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, Singapore, 138602.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Agilent Technologies, 1 Yishun Ave 7, Singapore, Singapore, 768923.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rajan</LastName><ForeName>Malini</ForeName><Initials>M</Initials><Identifier Source="ORCID">0000-0002-7653-4223</Identifier><AffiliationInfo><Affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hu</LastName><ForeName>Jennifer</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Celgene Corporation, 1616 Eastlake Ave East, Seattle, WA, 98102, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dedon</LastName><ForeName>Peter C</ForeName><Initials>PC</Initials><Identifier Source="ORCID">0000-0003-0011-3067</Identifier><AffiliationInfo><Affiliation>Antimicrobial Resistance Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, Singapore, 138602.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leibold</LastName><ForeName>Elizabeth A</ForeName><Initials>EA</Initials><Identifier Source="ORCID">0000-0003-1000-9503</Identifier><AffiliationInfo><Affiliation>Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA. betty.leibold@genetics.utah.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 GM045201</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 DK107712</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>U54 DK110858</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>T32 DK007115</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 ES002109</GrantID><Acronym>ES</Acronym><Agency>NIEHS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>01</Month><Day>15</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nat Commun</MedlineTA><NlmUniqueID>101528555</NlmUniqueID><ISSNLinking>2041-1723</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007328">Insulin</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007506">Iron-Sulfur Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D012357">RNA, Transfer, Lys</NameOfSubstance></Chemical><Chemical><RegistryNumber>9035-68-1</RegistryNumber><NameOfSubstance UI="D011384">Proinsulin</NameOfSubstance></Chemical><Chemical><RegistryNumber>E1UOL152H7</RegistryNumber><NameOfSubstance UI="D007501">Iron</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.1.1.-</RegistryNumber><NameOfSubstance UI="D012359">tRNA Methyltransferases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.8.4.5</RegistryNumber><NameOfSubstance UI="C559068">CDKAL1 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 4.2.1.3</RegistryNumber><NameOfSubstance UI="C000706488">Ireb2 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 4.2.1.3</RegistryNumber><NameOfSubstance UI="D035942">Iron Regulatory Protein 2</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018149" MajorTopicYN="N">Glucose Intolerance</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006706" MajorTopicYN="N">Homeostasis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007328" MajorTopicYN="N">Insulin</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D050417" MajorTopicYN="N">Insulin-Secreting Cells</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007340" MajorTopicYN="N">Insulinoma</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007501" MajorTopicYN="N">Iron</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D035942" MajorTopicYN="N">Iron Regulatory Protein 2</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007506" MajorTopicYN="N">Iron-Sulfur Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018345" MajorTopicYN="N">Mice, Knockout</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010190" MajorTopicYN="N">Pancreatic Neoplasms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011384" MajorTopicYN="N">Proinsulin</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012357" MajorTopicYN="N">RNA, Transfer, Lys</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D056811" MajorTopicYN="N">Unfolded Protein Response</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012359" MajorTopicYN="N">tRNA Methyltransferases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>12</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>12</Month><Day>06</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>1</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>1</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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Louis-et-Maximilien de Munich</li><li>Université nationale de Singapour</li><li>Université technique de Munich</li></orgName></list><tree><country name="États-Unis"><noRegion><name sortKey="Santos, Maria C Ferreira Dos" sort="Santos, Maria C Ferreira Dos" uniqKey="Santos M" first="Maria C Ferreira Dos" last="Santos">Maria C Ferreira Dos Santos</name></noRegion><name sortKey="Anderson, Cole P" sort="Anderson, Cole P" uniqKey="Anderson C" first="Cole P" last="Anderson">Cole P. Anderson</name><name sortKey="Anderson, Cole P" sort="Anderson, Cole P" uniqKey="Anderson C" first="Cole P" last="Anderson">Cole P. Anderson</name><name sortKey="Dedon, Peter C" sort="Dedon, Peter C" uniqKey="Dedon P" first="Peter C" last="Dedon">Peter C. Dedon</name><name sortKey="Hu, Jennifer" sort="Hu, Jennifer" uniqKey="Hu J" first="Jennifer" last="Hu">Jennifer Hu</name><name sortKey="Hu, Jennifer" sort="Hu, Jennifer" uniqKey="Hu J" first="Jennifer" last="Hu">Jennifer Hu</name><name sortKey="Leibold, Elizabeth A" sort="Leibold, Elizabeth A" uniqKey="Leibold E" first="Elizabeth A" last="Leibold">Elizabeth A. Leibold</name><name sortKey="Leibold, Elizabeth A" sort="Leibold, Elizabeth A" uniqKey="Leibold E" first="Elizabeth A" last="Leibold">Elizabeth A. Leibold</name><name sortKey="Leibold, Elizabeth A" sort="Leibold, Elizabeth A" uniqKey="Leibold E" first="Elizabeth A" last="Leibold">Elizabeth A. Leibold</name><name sortKey="Rajan, Malini" sort="Rajan, Malini" uniqKey="Rajan M" first="Malini" last="Rajan">Malini Rajan</name><name sortKey="Rajan, Malini" sort="Rajan, Malini" uniqKey="Rajan M" first="Malini" last="Rajan">Malini Rajan</name><name sortKey="Romney, Steven J" sort="Romney, Steven J" uniqKey="Romney S" first="Steven J" last="Romney">Steven J. Romney</name><name sortKey="Romney, Steven J" sort="Romney, Steven J" uniqKey="Romney S" first="Steven J" last="Romney">Steven J. Romney</name><name sortKey="Romney, Steven J" sort="Romney, Steven J" uniqKey="Romney S" first="Steven J" last="Romney">Steven J. Romney</name><name sortKey="Santos, Maria C Ferreira Dos" sort="Santos, Maria C Ferreira Dos" uniqKey="Santos M" first="Maria C Ferreira Dos" last="Santos">Maria C Ferreira Dos Santos</name><name sortKey="Zumbrennen Bullough, Kimberly B" sort="Zumbrennen Bullough, Kimberly B" uniqKey="Zumbrennen Bullough K" first="Kimberly B" last="Zumbrennen-Bullough">Kimberly B. Zumbrennen-Bullough</name><name sortKey="Zumbrennen Bullough, Kimberly B" sort="Zumbrennen Bullough, Kimberly B" uniqKey="Zumbrennen Bullough K" first="Kimberly B" last="Zumbrennen-Bullough">Kimberly B. Zumbrennen-Bullough</name></country><country name="Allemagne"><noRegion><name sortKey="Anderson, Cole P" sort="Anderson, Cole P" uniqKey="Anderson C" first="Cole P" last="Anderson">Cole P. Anderson</name></noRegion><name sortKey="De Angelis, Martin Hrabe" sort="De Angelis, Martin Hrabe" uniqKey="De Angelis M" first="Martin Hrabe" last="De Angelis">Martin Hrabe De Angelis</name><name sortKey="De Angelis, Martin Hrabe" sort="De Angelis, Martin Hrabe" uniqKey="De Angelis M" first="Martin Hrabe" last="De Angelis">Martin Hrabe De Angelis</name><name sortKey="De Angelis, Martin Hrabe" sort="De Angelis, Martin Hrabe" uniqKey="De Angelis M" first="Martin Hrabe" last="De Angelis">Martin Hrabe De Angelis</name><name sortKey="Fuchs, Helmut" sort="Fuchs, Helmut" uniqKey="Fuchs H" first="Helmut" last="Fuchs">Helmut Fuchs</name><name sortKey="Gailus Durner, Valerie" sort="Gailus Durner, Valerie" uniqKey="Gailus Durner V" first="Valerie" last="Gailus-Durner">Valerie Gailus-Durner</name><name sortKey="Kahle Stephan, Melanie" sort="Kahle Stephan, Melanie" uniqKey="Kahle Stephan M" first="Melanie" last="Kahle-Stephan">Melanie Kahle-Stephan</name><name sortKey="Kahle Stephan, Melanie" sort="Kahle Stephan, Melanie" uniqKey="Kahle Stephan M" first="Melanie" last="Kahle-Stephan">Melanie Kahle-Stephan</name><name sortKey="Neschen, Susanne" sort="Neschen, Susanne" uniqKey="Neschen S" first="Susanne" last="Neschen">Susanne Neschen</name><name sortKey="Neschen, Susanne" sort="Neschen, Susanne" uniqKey="Neschen S" first="Susanne" last="Neschen">Susanne Neschen</name><name sortKey="Rathkolb, Birgit" sort="Rathkolb, Birgit" uniqKey="Rathkolb B" first="Birgit" last="Rathkolb">Birgit Rathkolb</name><name sortKey="Rathkolb, Birgit" sort="Rathkolb, Birgit" uniqKey="Rathkolb B" first="Birgit" last="Rathkolb">Birgit Rathkolb</name><name sortKey="Rathkolb, Birgit" sort="Rathkolb, Birgit" uniqKey="Rathkolb B" first="Birgit" last="Rathkolb">Birgit Rathkolb</name><name sortKey="Rozman, Jan" sort="Rozman, Jan" uniqKey="Rozman J" first="Jan" last="Rozman">Jan Rozman</name><name sortKey="Rozman, Jan" sort="Rozman, Jan" uniqKey="Rozman J" first="Jan" last="Rozman">Jan Rozman</name><name sortKey="Wolf, Eckhard" sort="Wolf, Eckhard" uniqKey="Wolf E" first="Eckhard" last="Wolf">Eckhard Wolf</name></country><country name="République tchèque"><noRegion><name sortKey="Rozman, Jan" sort="Rozman, Jan" uniqKey="Rozman J" first="Jan" last="Rozman">Jan Rozman</name></noRegion></country><country name="Singapour"><noRegion><name sortKey="Cai, Weiling Maggie" sort="Cai, Weiling Maggie" uniqKey="Cai W" first="Weiling Maggie" last="Cai">Weiling Maggie Cai</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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