title: Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis.
abstract: 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.
authors.affiliation: Department 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, Harvard Medical School, Boston, United States.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Mancias
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Pontano Vaites
authors.affiliation: Gastroenterology 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.
authors.forename: Sahar
authors.initials: S
authors.lastname: Nissim
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Biancur
authors.affiliation: Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kim
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Gastroenterology 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 States.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D004920:Erythropoiesis; D005293:Ferritins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D056918:Nuclear Receptor Coactivators / Q000378:metabolism*; D010088:Oxidoreductases; D010588:Phagosomes / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases; D015027:Zebrafish
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D005293:Ferritins; D007501:Iron; C454461:FTH1 protein, human; D010088:Oxidoreductases; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: HERC2; NCOA4; autophagy; cell biology; erythropoiesis; human; iron metabolism; zebrafish