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 -