Ferritin mRNAs on rat liver membrane-bound polysomes synthesize ferritin that does not translocate across membranes

Tacchini, Lorenza; Rappocciolo, Emilia; Ferrero, Marina; Schiaffonati, Luisa; Cairo, Gaetano

doi:10.1016/0167-4781(92)90067-a

Cited by 13 publications

(9 citation statements)

References 41 publications

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“…The rapidity of this process suggests that amino acid determinants in nascent ferritin L are specifically recognized by a cellular constituent to target the normally cytosolic iron storage protein to the secretory pathway like the binding of signal sequences by signal recognition particle. Ferritin L, however, lacks a typical amino-terminal, hydrophobic signal sequence, and does not appear to enter the ER in vitro 48 ; how the protein enters the secretory pathway is not known. Future studies aimed at defining the sequence in ferritin L and its cognate cellular constituent that together direct export of this normally cytosolic protein could establish a new paradigm for protein secretion.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, the endoH resistance of N-glycosylated ferritin L is additional evidence that the protein traverses the Golgi apparatus. Since proteins typically enter the secretory pathway through a proteinaceous channel in the ER membrane and polysomes for ferritins have been isolated on this compartment, [48][49][50] it is likely that ferritin L enters the secretory pathway via the ER. Furthermore, the initial step of asparagine-linked glycosylation occurs in the ER lumen, so N-glycosylation of some ferritin L chains indicates their entry into this compartment.…”

Section: Discussionmentioning

confidence: 99%

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Regulated secretion of glycosylated human ferritin from hepatocytes

Ghosh

Hevi

Chuck

2004

Blood

117

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Serum ferritin has been used widely in clinical medicine chiefly as an indicator of iron stores and inflammation. Circulating ferritin also can have paracrine effects. Despite the clinical significance of serum ferritin, its secretion remains an enigma. The consensus view is that serum ferritin arises from tissue ferritinsprincipally ferritin light-which can be glycosylated. Ferritin heavy and light chains are cytosolic proteins that form cages of 24 subunits to store intracellular iron. We show that ferritin light is secreted when its expression is increased in stable, transfected HepG2 cells or adenovirus-infected HepG2 cells. Export occurs through the classical secretory pathway and some chains are N-glycosylated. Ferritins do not need to form cages prior to secretion. Secretion is blocked specifically, effectively, and rapidly by a factor in serum. The timing of this inhibition of ferritin secretion suggests that normally cytosolic ferritin L is targeted to the secretory pathway during translation despite the absence of a conventional signal sequence. Thus, secretion of glycosylated and unglycosylated ferritin is a regulated and not a stochastic process. IntroductionSerum ferritin has wide clinical utility primarily as an indicator of intracellular iron stores 1-3 and as an acute-phase reactant useful for the diagnosis and follow-up of adult Still disease 4 and systemic lupus erythematosis. 5,6 Elevated serum ferritin also has been used as a harbinger of tissue masses including ovarian carcinoma, 7 Hodgkin disease, 8 renal cell carcinoma, 9 and melanoma, 10 and preterm deliveries. 11,12 Ferritin has been linked to insulin resistance [13][14][15] and, controversially, to atherosclerosis. 16 Thus, serum ferritin has been used for the diagnosis and follow-up of numerous disorders, although it is most strongly linked to intracellular iron status and adult Still disease.Despite the frequent use in clinical medicine of measurements of serum ferritin, most aspects of its secretion remain unknown. An understanding of the mechanism and regulation of the secretion of ferritin would inform the use of this commonly used clinical test. Moreover, the trafficking of normally cytosolic ferritins is relevant to the physiology of iron homeostasis and the pathophysiology of many disorders in which intracellular ferritin could play a role. [17][18][19][20] There are 2 forms of ferritin that function together to store iron in cells. 2 In humans, ferritin light (L) has a molecular mass of 19 kDa and consists of 175 amino acids. Human ferritin L is 53% identical to ferritin heavy (H), which contains 183 amino acids and is 21 kDa. 21 Unlike ferritin L, ferritin H contains a ferroxidase site. Cages that store iron atoms are formed from 24 ferritin monomers in varying ratios of H/L. [21][22][23] Both ferritin H and L subunits are necessary for efficient iron storage; although ferritin L lacks a ferroxidase site, the protein nucleates iron mineralization. 21,24 Ferritin is secreted from liver 25,26 and lymphoid cells. 27 Some studies...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulated secretion of glycosylated human ferritin from hepatocytes

Ghosh

Hevi

Chuck

2004

Blood

117

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“…Serum ferritin is iron-poor and mainly consists of partially glycosylated L subunits, which suggests that they follow a classical secretary pathway through the endoplasmic reticulum and Golgi. However, although ferritin mRNAs are also present on membranebound polysomes [20], the protein does not have a recognisable signal peptide that could target it for secretion. L-ferritin secretion by hepatoma cells has only recently been molecularly characterised in detail [21,22].…”

Section: Extracellular Ferritinmentioning

confidence: 99%

New functions for an iron storage protein: The role of ferritin in immunity and autoimmunity

Recalcati

Invernizzi

Arosio

et al. 2008

Journal of Autoimmunity

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230

168

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“…11,12 However, it was never shown that serum ferritin was N-glycosylated, and ferritin did not enter the ER even when translated on rough ER. 13,14 Thus, the mechanism of ferritin secretion remains unclear. The question whether serum ferritin is actively secreted or leaked from damaged cells, the mechanism by which ferritin may be secreted and the cellular sources of serum ferritin remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Cohen

Gutiérrez

Weiss

et al. 2010

Blood

378

324

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The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of serum ferritin, we have used traditional and modern methodologies to characterize mouse serum ferritin. We find that both splenic macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells. Mouse serum ferritin is composed mostly of L-subunits, whereas it contains few H-subunits and iron content is low. L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17-kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that mouse serum ferritin is secreted through the nonclassical lysosomal secretory pathway. (Blood. 2010;116(9):1574-1584) IntroductionFerritin in mammals is a mostly intracellular, cytosolic iron storage and detoxification protein. It consists of H-and L-subunits that assemble into a 24-subunit hollow sphere in which iron is sequestered. 1 However, ferritin can also be detected extracellularly, in cerebrospinal fluid and sinovial fluid. In serum it is an extracellular ferritin that has been used extensively in diagnostic tests. In the clinical setting, serum ferritin evaluation is most commonly used to estimate body iron stores as low serum ferritin correlates with iron depletion, whereas high serum ferritin correlates with elevated body iron stores or with inflammation in patients with normal body iron stores. 2,3 Characterization of serum ferritin has produced many controversial results regarding subunit composition, iron content and other features. It has been compared in some studies to the "natural apoferritin" fraction found in many tissues, which is essentially devoid of iron 4 while other studies have claimed that serum ferritin contains considerable amounts of iron. 5 In insects, ferritin is a secreted protein composed of 2 types of subunits and the heteropolymer functions most likely as an iron transporter in the hemolymph. Each of the subunits has a classical secretion signal and ferritin is secreted from the insect fat body. 6 In contrast, mammalian H-and L-ferritin subunits lack signals mediating endoplasmic reticulum (ER) targeting, but ferritin can traffic to the lysosomal compartment through autophagy. 7 Binding of human serum ferritin to the lectin Concanavalin A (ConA) has previously suggested that ferritin is glycosylated 8,9 and actively secreted through the ER-Golgi pathway. 10 Indeed, it was shown in hepatocyte cell-models that inhibition of ER-Golgi trafficking abolished secretion o...

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Ferritin mRNAs on rat liver membrane-bound polysomes synthesize ferritin that does not translocate across membranes

Cited by 13 publications

References 41 publications

Regulated secretion of glycosylated human ferritin from hepatocytes

Regulated secretion of glycosylated human ferritin from hepatocytes

New functions for an iron storage protein: The role of ferritin in immunity and autoimmunity

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

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