Glycosyl Phosphatidylinositol-Anchored Ceruloplasmin Is Expressed by Rat Sertoli Cells and Is Concentrated in Detergent-Insoluble Membrane Fractions1

Fortna, Ryan R.; Watson, Hadiya A.; Nyquist, S. E.

doi:10.1095/biolreprod61.4.1042

Cited by 52 publications

(35 citation statements)

References 48 publications

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“…These metabolic studies accurately reflect newly synthesized holoceruloplasmin, because previous studies have shown that no copper is incorporated into previously synthesized apoceruloplasmin (23). The observation that GPI-linked ceruloplasmin also incorporates copper is consistent with studies demonstrating oxidase activity of this isoform in the rat (7,9). Interestingly, recent studies revealed that GPI-anchored proteins are sorted from other proteins within the ER early in the secretory pathway (32).…”

Section: Discussionsupporting

confidence: 86%

“…Consistent with this concept, in patients with Wilson disease, the absence or dysfunction of a copper-transporting ATPase abrogates copper transfer into the secretory pathway, resulting in marked diminution in the serum concentration of ceruloplasmin (4). Extrahepatic synthesis of human ceruloplasmin has been detected in several tissues, including the retina and brain (5,6), and recent studies in rodents suggest that in brain and testis ceruloplasmin is synthesized as a glycosylphosphatidylinositol (GPI) 1 -anchored form via alternative RNA splicing (7)(8)(9)(10).…”

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confidence: 88%

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Biochemical Analysis of a Missense Mutation in Aceruloplasminemia

Hellman¹,

Kono²,

Miyajima³

et al. 2002

Journal of Biological Chemistry

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Aceruloplasminemia is an inherited neurodegenerative disease characterized by parenchymal iron accumulation secondary to loss-of-function mutations in the ceruloplasmin gene. To elucidate the molecular pathogenesis of aceruloplasminemia, the biosynthesis of a missense mutant ceruloplasmin (P177R) occurring in an affected patient was examined. Chinese hamster ovary cells transfected with cDNAs encoding secreted and glycosylphosphatidylinositol (GPI)-linked wild-type or P177R human ceruloplasmin were examined by pulsechase metabolic labeling. These experiments, as well as immunofluorescent analysis and N-linked glycosylation studies, indicate that both the secreted and GPI-linked forms of the P177R mutant are retained in the endoplasmic reticulum (ER). The P177R mutation resides within a novel motif, which is repeated six times in human ceruloplasmin and is conserved in the homologous proteins hephaestin and factor VIII. Analysis of additional mutations in these motifs suggests a critical role for this region in ceruloplasmin trafficking and indicates that substitution of the arginine residue is critical to the ER retention of the P177R mutant. Metabolic labeling of transfected Chinese hamster ovary cells with 64 Cu indicates that the P177R mutant is retained in the ER as an apoprotein and that copper is incorporated into both secreted and GPI-linked ceruloplasmin as a late event in the secretory pathway. Taken together, these studies reveal new insights into the determinants of holoceruloplasmin biosynthesis and indicate that aceruloplasminemia can result from retention of mutant ceruloplasmin within the early secretory pathway.

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Section: Discussionsupporting

confidence: 86%

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confidence: 88%

Biochemical Analysis of a Missense Mutation in Aceruloplasminemia

Hellman¹,

Kono²,

Miyajima³

et al. 2002

Journal of Biological Chemistry

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“…In particular, a membrane-bound glycosylphosphatidylinositol (GPI)-anchored form of CP (GPI-CP) localized at the surface of mammalian astrocytes [28], rat leptomeningeal cells [29], and Sertoli cells [30] was reported. However, despite the detection of CP mRNA in immune cells [31,32], the characterization of the specific molecular isoform (s) expressed by huPBL has never been attempted.…”

Section: Introductionmentioning

confidence: 99%

Ceruloplasmin expression by human peripheral blood lymphocytes: A new link between immunity and iron metabolism

Banha

Marques

Palmeira‐de‐Oliveira

et al. 2008

Free Radical Biology and Medicine

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Ceruloplasmin (CP) is a multicopper oxidase involved in the acute phase reaction to stress. Although the physiological role of CP is uncertain, its role in iron (Fe) homeostasis and protection against free radical-initiated cell injury has been widely documented. Previous studies showed the existence of two molecular isoforms of CP: secreted CP (sCP) and a membrane glycosylphosphatidylinositol (GPI)-anchored form of CP (GPI-CP). sCP is produced mainly by the liver and is abundant in human serum whereas GPI-CP is expressed in mammalian astrocytes, rat leptomeningeal cells, and Sertolli cells. Herein, we show using RT-PCR that human peripheral blood lymphocytes (huPBL) constitutively express the transcripts for both CP molecular isoforms previously reported. Also, expression of CP in huPBL is demonstrated by immunofluorescence with confocal microscopy and flow cytometry analysis using cells isolated from healthy blood donors with normal Fe status. Importantly, the results obtained show that natural killer cells have a significantly higher CP expression compared to all other major lymphocyte subsets. In this context, the involvement of lymphocyte-derived CP on host defense processes via its anti/prooxidant properties is proposed, giving further support for a close functional interaction between the immune system and the Fe metabolism.

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“…In addition to transferrin and TfR1, other proteins involved in iron transport, such as DMT1 and glycosyl phosphatidylinositol-anchored ceruloplasmin (11,13,42,46), and iron storage, such as cytosolic and mitochondrial ferritin, were found in the testis. DMT1 is suggested to be expressed in a stage-dependent manner in the elongating spermatids and in the cytosol and nuclei of SC of adult rat testis, where it may play a role in iron uptake (13), but the source of this iron has not been identified so far.…”

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confidence: 99%

“…The mRNA analysis of cytosolic ferritin showed that transcript levels of the ferritin H-subunit were significantly higher than L-subunits, and in the cell types analyzed the highest expression was found in PTM and SC, followed by the early spermatocytes and decreasing as spermatocytes mature (Table 1; also see http://public.wsu.edu/ ϳgriswold/microarray/). Cellular localization of glycosyl phosphatidylinositol-anchored ceruloplasmin has never been determined (11,46).…”

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confidence: 99%

Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload

Leichtmann‐Bardoogo

Cohen

Weiss

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The universal importance of iron, its high toxicity, and complex chemistry present a challenge to biological systems in general and to protected compartments in particular. The high mitotic rate and avid mitochondriogenesis of developing male germ cells imply high iron requirements. Yet access to germ cells is tightly regulated by the blood-testis barrier that protects the meiotic and postmeiotic germ cells. To elucidate how iron is supplied to developing male germ cells, we analyzed iron deposition and iron transport proteins in testes of mice with iron overload and with genetic ablation of the iron regulators Hfe and iron regulatory protein 2. Iron accumulated mainly around seminiferous tubules, and only small amounts localized within the seminiferous tubules. The localization and regulation of proteins involved in iron import, storage, and export such as transferrin, transferrin receptor, the divalent metal transporter-1, cytosolic ferritin, and ferroportin strongly support a model of a largely autonomous iron cycle within seminiferous tubules. We show evidence that ferritin secretion from Sertoli cells may play an important role in iron acquisition of primary spermatocytes. During spermatogenic development iron is carried along from primary spermatocytes to spermatids, and from spermatids iron is recycled to the apical compartment of Sertoli cells, which traffic it back to a new generation of spermatocytes. Losses are replenished by the peripheral circulation. Such an internal iron cycle essentially detaches the iron homeostasis within the seminiferous tubule from the periphery and protects developing germ cells from iron fluctuations. This model explains how compartmentalization can optimize cellular and systemic nutrient homeostasis.

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Glycosyl Phosphatidylinositol-Anchored Ceruloplasmin Is Expressed by Rat Sertoli Cells and Is Concentrated in Detergent-Insoluble Membrane Fractions1

Cited by 52 publications

References 48 publications

Biochemical Analysis of a Missense Mutation in Aceruloplasminemia

Biochemical Analysis of a Missense Mutation in Aceruloplasminemia

Ceruloplasmin expression by human peripheral blood lymphocytes: A new link between immunity and iron metabolism

Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload

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