Ferritin is secreted via 2 distinct nonclassical vesicular pathways.

Autor:	Truman-Rosentsvit M; Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Berenbaum D; Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Spektor L; Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Cohen LA; Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Belizowsky-Moshe S; Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Lifshitz L; Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Ma J; Center for Medical Genetics, Beijing Children's Hospital, Capital Medical University, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing, China., Li W; Center for Medical Genetics, Beijing Children's Hospital, Capital Medical University, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing, China., Kesselman E; CryoEM Laboratory of Soft Matter, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Abutbul-Ionita I; CryoEM Laboratory of Soft Matter, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Danino D; CryoEM Laboratory of Soft Matter, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel., Gutierrez L; Departamento de Química Analítica, Instituto de Nanociencia de Aragón, Universidad de Zaragoza, Zaragoza, Spain., Li H; Medical School of Nanjing University, Nanjing, China., Li K; Medical School of Nanjing University, Nanjing, China., Lou H; Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China., Regoni M; Department of Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy., Poli M; Department of Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy., Glaser F; The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion, Technion City, Haifa, Israel; and., Rouault TA; Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD., Meyron-Holtz EG; Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2018 Jan 18; Vol. 131 (3), pp. 342-352. Date of Electronic Publication: 2017 Oct 26.
DOI:	10.1182/blood-2017-02-768580
Abstrakt:	Ferritin turnover plays a major role in tissue iron homeostasis, and ferritin malfunction is associated with impaired iron homeostasis and neurodegenerative diseases. In most eukaryotes, ferritin is considered an intracellular protein that stores iron in a nontoxic and bioavailable form. In insects, ferritin is a classically secreted protein and plays a major role in systemic iron distribution. Mammalian ferritin lacks the signal peptide for classical endoplasmic reticulum-Golgi secretion but is found in serum and is secreted via a nonclassical lysosomal secretion pathway. This study applied bioinformatics and biochemical tools, alongside a protein trafficking mouse models, to characterize the mechanisms of ferritin secretion. Ferritin trafficking via the classical secretion pathway was ruled out, and a 2:1 distribution of intracellular ferritin between membrane-bound compartments and the cytosol was observed, suggesting a role for ferritin in the vesicular compartments of the cell. Focusing on nonclassical secretion, we analyzed mouse models of impaired endolysosomal trafficking and found that ferritin secretion was decreased by a BLOC-1 mutation but increased by BLOC-2, BLOC-3, and Rab27A mutations of the cellular trafficking machinery, suggesting multiple export routes. A 13-amino-acid motif unique to ferritins that lack the secretion signal peptide was identified on the BC-loop of both subunits and plays a role in the regulation of ferritin secretion. Finally, we provide evidence that secretion of iron-rich ferritin was mediated via the multivesicular body-exosome pathway. These results enhance our understanding of the mechanism of ferritin secretion, which is an important piece in the puzzle of tissue iron homeostasis.
Databáze:	MEDLINE
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