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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. 

Web URL: Read this and other abstracts on PubMed here


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.