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Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification
MCFD. Santos, CP. Anderson, S. Neschen, KB. Zumbrennen-Bullough, SJ. Romney, M. Kahle-Stephan, B. Rathkolb, V. Gailus-Durner, H. Fuchs, E. Wolf, J. Rozman, MH. de Angelis, WM. Cai, M. Rajan, J. Hu, PC. Dedon, EA. Leibold,
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
R01 GM045201
NIGMS NIH HHS - United States
R01 DK107712
NIDDK NIH HHS - United States
U54 DK110858
NIDDK NIH HHS - United States
T32 DK007115
NIDDK NIH HHS - United States
P30 ES002109
NIEHS NIH HHS - United States
NLK
Directory of Open Access Journals
od 2015
Free Medical Journals
od 2010
PubMed Central
od 2012
Europe PubMed Central
od 2012
ProQuest Central
od 2019-01-01
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
Medline Complete (EBSCOhost)
od 2012-11-01
Health & Medicine (ProQuest)
od 2019-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2010
Springer Nature OA/Free Journals
od 2010-12-01
Springer Nature - nature.com Journals - Fully Open Access
od 2010-12-01
- MeSH
- beta-buňky metabolismus MeSH
- homeostáza MeSH
- inzulin metabolismus MeSH
- inzulinom genetika metabolismus MeSH
- krysa rodu rattus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- nádorové buněčné linie MeSH
- nádory slinivky břišní genetika metabolismus MeSH
- porucha glukózové tolerance genetika MeSH
- proinsulin genetika metabolismus MeSH
- proteiny obsahující železo a síru metabolismus MeSH
- regulační protein železa 2 genetika metabolismus MeSH
- RNA transferová Lys genetika metabolismus MeSH
- signální dráha UPR genetika MeSH
- tRNA-methyltransferasy genetika metabolismus MeSH
- železo metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Citace poskytuje Crossref.org
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- $a Santos, Maria C Ferreira Dos $u Department of Medicine, Division of Hematology, University of Utah, Salt Lake City, UT, 84112, USA. Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.
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- $a 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.
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- $a Anderson, Cole P $u Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA. Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA. Landstuhl Regional Medical Center, 66849, Landstuhl, Germany.
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- $a Kahle-Stephan, Melanie $u German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany. Medizinische Hochschule Brandenburg Theodor Fontane Institut für Sozialmedizin und Epidemiologie, 14770, Brandenburg an der Havel, Germany.
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- $a Rathkolb, Birgit $u German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany. German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen Strasse 25, 81377, Munich, Germany.
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- $a Cai, Weiling Maggie $u Department of Microbiology, National University of Singapore, Singapore, Singapore, 119077. Antimicrobial Resistance Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore, Singapore, 138602. Agilent Technologies, 1 Yishun Ave 7, Singapore, Singapore, 768923.
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