Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis
NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/10308 |
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| author | Joseph D Mancias Laura Pontano Vaites Sahar Nissim Douglas E Biancur Andrew J Kim Xiaoxu Wang Yu Liu Wolfram Goessling Alec C Kimmelman J Wade Harper |
| author_facet | Joseph D Mancias Laura Pontano Vaites Sahar Nissim Douglas E Biancur Andrew J Kim Xiaoxu Wang Yu Liu Wolfram Goessling Alec C Kimmelman J Wade Harper |
| author_sort | Joseph D Mancias |
| collection | DOAJ |
| description | NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4-FTH1 interaction, we demonstrate that direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes. Moreover, NCOA4 abundance is under dual control via autophagy and the ubiquitin proteasome system. Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. In zebrafish and cultured cells, NCOA4 plays an essential role in erythroid differentiation. This work reveals the molecular nature of the NCOA4-ferritin complex and explains how intracellular iron levels modulate NCOA4-mediated ferritinophagy in cells and in an iron-dependent physiological setting. |
| first_indexed | 2024-04-14T07:47:05Z |
| format | Article |
| id | doaj.art-5af6e8d673d04762ad593f5eaec09092 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:47:05Z |
| publishDate | 2015-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5af6e8d673d04762ad593f5eaec090922022-12-22T02:05:18ZengeLife Sciences Publications LtdeLife2050-084X2015-10-01410.7554/eLife.10308Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysisJoseph D Mancias0Laura Pontano Vaites1Sahar Nissim2Douglas E Biancur3Andrew J Kim4Xiaoxu Wang5Yu Liu6Wolfram Goessling7Alec C Kimmelman8J Wade Harper9Department of Cell Biology, Harvard Medical School, Boston, United States; Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States; Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, United StatesDepartment of Cell Biology, Harvard Medical School, Boston, United StatesGastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Genetics Division, Brigham and Women's Hospital, Boston, United States; Dana-Farber Cancer Institute, Boston, United StatesDivision of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United StatesGastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, United StatesDivision of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United StatesDepartment of Cell Biology, Harvard Medical School, Boston, United StatesGastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Genetics Division, Brigham and Women's Hospital, Boston, United States; Dana-Farber Cancer Institute, Boston, United States; Harvard Stem Cell Institute, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United StatesDivision of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United StatesDepartment of Cell Biology, Harvard Medical School, Boston, United StatesNCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4-FTH1 interaction, we demonstrate that direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes. Moreover, NCOA4 abundance is under dual control via autophagy and the ubiquitin proteasome system. Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. In zebrafish and cultured cells, NCOA4 plays an essential role in erythroid differentiation. This work reveals the molecular nature of the NCOA4-ferritin complex and explains how intracellular iron levels modulate NCOA4-mediated ferritinophagy in cells and in an iron-dependent physiological setting.https://elifesciences.org/articles/10308NCOA4autophagyiron metabolismerythropoiesisHERC2 |
| spellingShingle | Joseph D Mancias Laura Pontano Vaites Sahar Nissim Douglas E Biancur Andrew J Kim Xiaoxu Wang Yu Liu Wolfram Goessling Alec C Kimmelman J Wade Harper Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis eLife NCOA4 autophagy iron metabolism erythropoiesis HERC2 |
| title | Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis |
| title_full | Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis |
| title_fullStr | Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis |
| title_full_unstemmed | Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis |
| title_short | Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis |
| title_sort | ferritinophagy via ncoa4 is required for erythropoiesis and is regulated by iron dependent herc2 mediated proteolysis |
| topic | NCOA4 autophagy iron metabolism erythropoiesis HERC2 |
| url | https://elifesciences.org/articles/10308 |
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