Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification
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...
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| Formaat: | Artikel |
| Taal: | English |
| Gepubliceerd in: |
Springer Science and Business Media LLC
2020
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| Online toegang: | https://hdl.handle.net/1721.1/126282 |
| _version_ | 1826201963476287488 |
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| author | Santos, Maria C. Ferreira dos Anderson, Cole P. Neschen, Susanne Zumbrennen-Bullough, Kimberly B. Romney, Steven J. Kahle-Stephan, Melanie Rathkolb, Birgit Gailus-Durner, Valerie Fuchs, Helmut Wolf, Eckhard Rozman, Jan de Angelis, Martin Hrabe Cai, Weiling Maggie Rajan, Malini Hu, Jennifer Dedon, Peter C Leibold, Elizabeth A. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Santos, Maria C. Ferreira dos Anderson, Cole P. Neschen, Susanne Zumbrennen-Bullough, Kimberly B. Romney, Steven J. Kahle-Stephan, Melanie Rathkolb, Birgit Gailus-Durner, Valerie Fuchs, Helmut Wolf, Eckhard Rozman, Jan de Angelis, Martin Hrabe Cai, Weiling Maggie Rajan, Malini Hu, Jennifer Dedon, Peter C Leibold, Elizabeth A. |
| author_sort | Santos, Maria C. Ferreira dos |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:59:46Z |
| format | Article |
| id | mit-1721.1/126282 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:59:46Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1262822022-09-27T23:23:11Z Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification Santos, Maria C. Ferreira dos Anderson, Cole P. Neschen, Susanne Zumbrennen-Bullough, Kimberly B. Romney, Steven J. Kahle-Stephan, Melanie Rathkolb, Birgit Gailus-Durner, Valerie Fuchs, Helmut Wolf, Eckhard Rozman, Jan de Angelis, Martin Hrabe Cai, Weiling Maggie Rajan, Malini Hu, Jennifer Dedon, Peter C Leibold, Elizabeth A. Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Biological Engineering 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. 2020-07-21T18:18:44Z 2020-07-21T18:18:44Z 2020-01 2018-12 2020-03-05T17:49:34Z Article http://purl.org/eprint/type/JournalArticle 2041-1723 https://hdl.handle.net/1721.1/126282 Ferreira dos Santos, Maria C. et al. "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification." Nature Communications 11, 1 (January 2020): 296 © 2020 The Author(s) en http://dx.doi.org/10.1038/s41467-019-14004-5 Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Santos, Maria C. Ferreira dos Anderson, Cole P. Neschen, Susanne Zumbrennen-Bullough, Kimberly B. Romney, Steven J. Kahle-Stephan, Melanie Rathkolb, Birgit Gailus-Durner, Valerie Fuchs, Helmut Wolf, Eckhard Rozman, Jan de Angelis, Martin Hrabe Cai, Weiling Maggie Rajan, Malini Hu, Jennifer Dedon, Peter C Leibold, Elizabeth A. Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification |
| title | Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification |
| title_full | Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification |
| title_fullStr | Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification |
| title_full_unstemmed | Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification |
| title_short | Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification |
| title_sort | irp2 regulates insulin production through iron mediated cdkal1 catalyzed trna modification |
| url | https://hdl.handle.net/1721.1/126282 |
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