Ferritin is secreted via two distinct non-classical vesicular pathways

Marianna Truman-Rosentsvit, Dina Berenbaum, Lior Spektor, Lyora A. Cohen, Shirly Belizowsky-Moshe, Lena Lifshitz, Jing Ma, Wei Li, Ellina Kesselman, Inbal Abutbul-Ionita, Dganit Danino, Lucia Gutierrez, Huihui Li, Kuanyu Li, Huifang Lou, Maria Regoni, Maura Poli, Fabian Glaser, Tracey A. Rouault and Esther G. Meyron-Holtz

Key points

  • Iron-loaded ferritin is secreted via both the non-classical secretory-autophagy and the multivesicular-body-exosome pathways.

  • A motif on both ferritin subunits is involved in the regulation of ferritin secretion.


Ferritin turnover plays a major role in tissue iron homeostasis and ferritin misfunction is associated with impaired iron homeostasis and neurodegenerative diseases. In most eukaryotes, ferritin is considered an intracellular protein that stores iron in a non-toxic and bio-available 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 ER-Golgi secretion but is found in serum and is secreted via a non-classical 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 non-classical secretion, we analyzed mouse models of impaired endo-lysosomal trafficking and found that ferritin secretion was decreased by a BLOC-1 mutation but increased by BLOC-2, -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.

  • Submitted February 17, 2017.
  • Accepted October 18, 2017.