Ferritin is secreted via 2 distinct nonclassical vesicular pathways
Truman-Rosentsvit M, Berenbaum D, Spektor L, Cohen LA, Belizowsky-Moshe S, Lifshitz L, Ma J, Li W, Kesselman E, Abutbul-Ionita I, Danino D, Gutierrez L, Li H, Li K, Lou H, Regoni M, Poli M, Glaser F, Rouault TA, Meyron-Holtz EG (2018) Blood. 2018 Jan;131(3): 342-352. doi: 10.1182/blood-2017-02-768580. Epub 2017 Oct 26.
Abstract:
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 ferritinsecretion 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 ferritinsecretion, which is an important piece in the puzzle of tissue iron homeostasis.
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