scholarly journals Augmenter of Liver Regeneration regulates cellular iron homeostatis by modulating mitochondrial transport of ATP-binding cassette B8

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hsiang-Chun Chang ◽  
Jason Solomon Shapiro ◽  
Xinghang Jiang ◽  
Grant Senyei ◽  
Teruki Sato ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Mammalian Cells ◽  
Protein Import ◽  
Regulatory Protein ◽  
Atp Binding ◽  
Physical Interaction ◽  
Mitochondrial Import ◽  
Cellular Iron ◽  
Augmenter Of Liver Regeneration ◽  
Atp Binding Cassette

Chronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts, however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40/ALR protein import pathway, results in impaired cytosolic Fe/S cluster biogenesis in mammalian cells. Mechanistically, MIA40/ALR facilitates the mitochondrial import of ATP binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding provides a mechanistic link between MIA40/ALR import machinery and cytosolic Fe/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.

scholarly journals Augmenter of Liver Regeneration Regulates Cellular Iron Homeostasis by Modulating Mitochondrial Transport of ATP-Binding Cassette B8

2020 ◽  
Author(s):  
Hsiang-Chun Chang ◽  
Jason S. Shapiro ◽  
Xinghang Jiang ◽  
Grant Senyei ◽  
Teruki Sato ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Mammalian Cells ◽  
Protein Import ◽  
Regulatory Protein ◽  
Atp Binding ◽  
Physical Interaction ◽  
Mitochondrial Import ◽  
Cellular Iron ◽  
Augmenter Of Liver Regeneration ◽  
Atp Binding Cassette

AbstractChronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts, however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40/ALR protein import pathway, results in impaired cytosolic Fe/S cluster biogenesis in mammalian cells. Mechanistically, MIA40/ALR facilitates the mitochondrial import of ATP binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding provides a mechanistic link between MIA40/ALR import machinery and cytosolic Fe/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.

Co-operative function and mutual stabilization of the half ATP-binding cassette transporters HAF-4 and HAF-9 in Caenorhabditis elegans

2013 ◽  
Vol 452 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Takahiro Tanji ◽  
Kenji Nishikori ◽  
Hirohisa Shiraishi ◽  
Masatomo Maeda ◽  
Ayako Ohashi-Kobayashi
Keyword(s):  
Caenorhabditis Elegans ◽  
Antigen Processing ◽  
Fluorescent Protein ◽  
Peptide Transporter ◽  
Deletion Mutants ◽  
Atp Binding ◽  
Physical Interaction ◽  
Atp Binding Cassette Transporters ◽  
Green Fluorescent ◽  
Atp Binding Cassette

Caenorhabditis elegans HAF-4 and HAF-9 are half ABC (ATP-binding-cassette) transporters that are highly homologous to the human lysosomal peptide transporter TAPL [TAP (transporter associated with antigen processing)-like; ABCB9]. We reported previously that both HAF-4 and HAF-9 localize to the membrane of a subset of intestinal organelles, and are required for the formation of these organelles and other physiological aspects. In the present paper, we report the genetic and physical interactions between HAF-4 and HAF-9. Overexpression of HAF-4 and HAF-9 did not rescue the intestinal organelle defect of the haf-9 and haf-4 deletion mutants respectively, indicating that they cannot substitute for each other. Double haf-4 and haf-9 mutants do not exhibit more severe phenotypes than the single mutants, suggesting their co-operative function. Immunoprecipitation experiments demonstrated their physical interaction. The results of the present study suggest that HAF-4 and HAF-9 form a heterodimer. Furthermore, Western blot analysis of the deletion mutants and RNAi (RNA interference) knockdown experiments in GFP (green fluorescent protein)-tagged HAF-4 or HAF-9 transgenic worms suggest that HAF-4–HAF-9 heterodimer formation is required for their stabilization. The findings provide a clue as to how ABC transporters adopt a stable functional form.

scholarly journals Regulation of cellular iron metabolism

2011 ◽  
Vol 434 (3) ◽  
pp. 365-381 ◽  
Author(s):  
Jian Wang ◽  
Kostas Pantopoulos
Keyword(s):  
Iron Metabolism ◽  
Mammalian Cells ◽  
Regulatory Protein ◽  
Cell Types ◽  
Excess Iron ◽  
Cellular Iron ◽  
System A ◽  
Regulatory Circuit ◽  
Transcriptional Regulatory ◽  
Responsive Element

Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron–sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance.

scholarly journals Human Nbp35 Is Essential for both Cytosolic Iron-Sulfur Protein Assembly and Iron Homeostasis

2008 ◽  
Vol 28 (17) ◽  
pp. 5517-5528 ◽  
Author(s):  
Oliver Stehling ◽  
Daili J. A. Netz ◽  
Brigitte Niggemeyer ◽  
Ralf Rösser ◽  
Richard S. Eisenstein ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Protein Assembly ◽  
Cluster Assembly ◽  
S Protein ◽  
Cellular Iron ◽  
Iron Sulfur ◽  
S Proteins

ABSTRACT The maturation of cytosolic iron-sulfur (Fe/S) proteins in mammalian cells requires components of the mitochondrial iron-sulfur cluster assembly and export machineries. Little is known about the cytosolic components that may facilitate the assembly process. Here, we identified the cytosolic soluble P-loop NTPase termed huNbp35 (also known as Nubp1) as an Fe/S protein, and we defined its role in the maturation of Fe/S proteins in HeLa cells. Depletion of huNbp35 by RNA interference decreased cell growth considerably, indicating its essential function. The deficiency in huNbp35 was associated with an impaired maturation of the cytosolic Fe/S proteins glutamine phosphoribosylpyrophosphate amidotransferase and iron regulatory protein 1 (IRP1), while mitochondrial Fe/S proteins remained intact. Consequently, huNbp35 is specifically involved in the formation of extramitochondrial Fe/S proteins. The impaired maturation of IRP1 upon huNbp35 depletion had profound consequences for cellular iron metabolism, leading to decreased cellular H-ferritin, increased transferrin receptor levels, and higher transferrin uptake. These properties clearly distinguished huNbp35 from its yeast counterpart Nbp35, which is essential for cytosolic-nuclear Fe/S protein assembly but plays no role in iron regulation. huNbp35 formed a complex with its close homologue huCfd1 (also known as Nubp2) in vivo, suggesting the existence of a heteromeric P-loop NTPase complex that is required for both cytosolic Fe/S protein assembly and cellular iron homeostasis.

scholarly journals Cooperative Interaction between Hepatocyte Nuclear Factor 4α and GATA Transcription Factors Regulates ATP-Binding Cassette Sterol Transporters ABCG5 and ABCG8

2007 ◽  
Vol 27 (12) ◽  
pp. 4248-4260 ◽  
Author(s):  
Koichi Sumi ◽  
Toshiya Tanaka ◽  
Aoi Uchida ◽  
Kenta Magoori ◽  
Yasuyo Urashima ◽  
...  
Keyword(s):  
Cholesterol Homeostasis ◽  
Cooperative Interaction ◽  
Atp Binding ◽  
Physical Interaction ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Gata Factors ◽  
Synergistic Activation ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Atp Binding Cassette

ABSTRACT Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4α (HNF4α) in the ABCG5/ABCG8 intergenic promoter, through which HNF4α strongly activated the expression of a reporter gene in both directions. The HNF4α-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4α. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4α leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4α and GATA were essential for maximal synergism. We also show that HNF4α, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4α and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4α acts synergistically with GATA factors to activate gene expression in a bidirectional fashion.

scholarly journals Switching of the homooligomeric ATP-binding cassette transport complex MDL1 from post-translational mitochondrial import to endoplasmic reticulum insertion

FEBS Journal ◽  
2007 ◽  
Vol 274 (20) ◽  
pp. 5298-5310 ◽  
Author(s):  
Simone Gompf ◽  
Ariane Zutz ◽  
Matthias Hofacker ◽  
Winfried Haase ◽  
Chris van der Does ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Atp Binding ◽  
Mitochondrial Import ◽  
Transport Complex ◽  
Atp Binding Cassette

scholarly journals Regulation of Transcription Factor Pdr1p Function by an Hsp70 Protein in Saccharomyces cerevisiae

1998 ◽  
Vol 18 (3) ◽  
pp. 1147-1155 ◽  
Author(s):  
Timothy C. Hallstrom ◽  
David J. Katzmann ◽  
Rodrigo J. Torres ◽  
W. John Sharp ◽  
W. Scott Moye-Rowley
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Transcription Factor ◽  
Regulatory Protein ◽  
Atp Binding ◽  
Regulation Of Transcription ◽  
Pleiotropic Drug Resistance ◽  
Atp Binding Cassette Transporter ◽  
Encoding Genes ◽  
Atp Binding Cassette

ABSTRACT Multiple or pleiotropic drug resistance in the yeastSaccharomyces cerevisiae requires the expression of several ATP binding cassette transporter-encoding genes under the control of the zinc finger-containing transcription factor Pdr1p. The ATP binding cassette transporter-encoding genes regulated by Pdr1p include PDR5 and YOR1, which are required for normal cycloheximide and oligomycin tolerances, respectively. We have isolated a new member of the PDR gene family that encodes a member of the Hsp70 family of proteins found in this organism. This gene has been designated PDR13 and is required for normal growth. Overexpression of Pdr13p leads to an increase in both the expression of PDR5 and YOR1 and a corresponding enhancement in drug resistance. Pdr13p requires the presence of both the PDR1 structural gene and the Pdr1p binding sites in target promoters to mediate its effect on drug resistance and gene expression. A dominant, gain-of-function mutant allele ofPDR13 was isolated and shown to have the same phenotypic effects as when the gene is present on a 2μm plasmid. Genetic and Western blotting experiments indicated that Pdr13p exerts its effect on Pdr1p at a posttranslational step. These data support the view that Pdr13p influences pleiotropic drug resistance by enhancing the function of the transcriptional regulatory protein Pdr1p.

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