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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,
Language English Country Great Britain
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
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
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- MeSH
- Insulin-Secreting Cells metabolism MeSH
- Homeostasis MeSH
- Insulin metabolism MeSH
- Insulinoma genetics metabolism MeSH
- Rats MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Cell Line, Tumor MeSH
- Pancreatic Neoplasms genetics metabolism MeSH
- Glucose Intolerance genetics MeSH
- Proinsulin genetics metabolism MeSH
- Iron-Sulfur Proteins metabolism MeSH
- Iron Regulatory Protein 2 genetics metabolism MeSH
- RNA, Transfer, Lys genetics metabolism MeSH
- Unfolded Protein Response genetics MeSH
- tRNA Methyltransferases genetics metabolism MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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.
References provided by 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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