期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-14004-5
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资金
- National Institute of Health (NIH) [R01GM045201, R01DK107712]
- University of Utah SEED grant
- NIH [R01GM070641, R01ES026856, R01ES024615, P30ES002109]
- National Research Foundation of Singapore through the Singapore-MIT Alliance for Research and Technology
- SMA3 Programme Fellowship
- Hematology Training Program [T32DK007115]
- NIEHS Toxicology Training grant [T32ES007020]
- American Diabetes Association Minority Postdoctoral Fellowship Award [1-18-PMF-020]
- NIDDK Cooperative Hematology Specialized Core Center [1U54DK110858]
- German Federal Ministry of Education and Research Infrafrontier grant [01KX1012]
- German Center for Diabetes Research
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 beta cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t(6)A37 in tRNA(UUU)(Lys) to ms(2)t(6)A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms(2)t(6)A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2(-/-) beta 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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