Ferritin is secreted via 2 distinct nonclassical 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; Esther G. Meyron-Holtz

doi:10.1182/blood-2017-02-768580

Ferritin is secreted via 2 distinct nonclassical 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, Esther G. Meyron-Holtz^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

142 Scopus citations

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 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.

Original language	English
Pages (from-to)	342-352
Number of pages	11
Journal	Blood
Volume	131
Issue number	3
DOIs	https://doi.org/10.1182/blood-2017-02-768580
State	Published - 18 Jan 2018
Externally published	Yes

Access to Document

10.1182/blood-2017-02-768580

Cite this

Truman-Rosentsvit, M., Berenbaum, D., Spektor, L., Cohen, L. A., 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, T. A., & Meyron-Holtz, E. G. (2018). Ferritin is secreted via 2 distinct nonclassical vesicular pathways. Blood, 131(3), 342-352. https://doi.org/10.1182/blood-2017-02-768580

@article{53085400b81f4ceb99e5b7132138f2f3,

title = "Ferritin is secreted via 2 distinct nonclassical vesicular pathways",

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 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.",

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

note = "Funding Information: L.G. acknowledges financial support from the Ram{\'o}n y Cajal subprogram (RYC-2014-15512). This research was supported by The Israel Science Foundation (grant 1444/13 to E.G.M.-H.), the US–Israel Binational Science Foundation (grant 2007466 to E.G.M.-H. and T.A.R.), and the National Science Foundation of China (grants 91539204 and 31230046 to W.L.).",

year = "2018",

month = jan,

day = "18",

doi = "10.1182/blood-2017-02-768580",

language = "英语",

volume = "131",

pages = "342--352",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "3",

}

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, 'Ferritin is secreted via 2 distinct nonclassical vesicular pathways', Blood, vol. 131, no. 3, pp. 342-352. https://doi.org/10.1182/blood-2017-02-768580

TY - JOUR

T1 - Ferritin is secreted via 2 distinct nonclassical vesicular pathways

AU - Truman-Rosentsvit, Marianna

AU - Berenbaum, Dina

AU - Spektor, Lior

AU - Cohen, Lyora A.

AU - Belizowsky-Moshe, Shirly

AU - Lifshitz, Lena

AU - Ma, Jing

AU - Li, Wei

AU - Kesselman, Ellina

AU - Abutbul-Ionita, Inbal

AU - Danino, Dganit

AU - Gutierrez, Lucia

AU - Li, Huihui

AU - Li, Kuanyu

AU - Lou, Huifang

AU - Regoni, Maria

AU - Poli, Maura

AU - Glaser, Fabian

AU - Rouault, Tracey A.

AU - Meyron-Holtz, Esther G.

N1 - Funding Information: L.G. acknowledges financial support from the Ramón y Cajal subprogram (RYC-2014-15512). This research was supported by The Israel Science Foundation (grant 1444/13 to E.G.M.-H.), the US–Israel Binational Science Foundation (grant 2007466 to E.G.M.-H. and T.A.R.), and the National Science Foundation of China (grants 91539204 and 31230046 to W.L.).

PY - 2018/1/18

Y1 - 2018/1/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040817775&partnerID=8YFLogxK

U2 - 10.1182/blood-2017-02-768580

DO - 10.1182/blood-2017-02-768580

M3 - 文章

C2 - 29074498

AN - SCOPUS:85040817775

SN - 0006-4971

VL - 131

SP - 342

EP - 352

JO - Blood

JF - Blood

IS - 3

ER -

Ferritin is secreted via 2 distinct nonclassical vesicular pathways

Abstract

Access to Document

Other files and links

Fingerprint

Cite this