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ABC Transporters in Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 90213

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Special Issue Editor

French Institute of Health and Medical Research, Inserm, Paris-Saclay University, Faculty of Science, Rue des Adèles, Bâtiment 440, Orsay, France
Interests: ABC transporters; cell biology; cell models; bile secretion; rare cholestatic diseases; targeted pharmacotherapy

Special Issue Information

Dear colleagues,

Mammalian ATP-binding cassette (ABC) transporters constitute a superfamily of proteins involved in many essential cellular processes. Most of these are transmembrane proteins and allow the active transport of solutes, small molecules, and lipids across biological membranes. On the one hand, some of these transporters are involved in drug resistance (also referred to as MDR or multidrug resistance), a process known to be a major brake in most anticancer treatments, and the medical challenge is thus to specifically inhibit their function. On the other hand, molecular defects in some of these ABC transporters are correlated with several rare human diseases, the most well-documented of which being cystic fibrosis, which is caused by genetic variations in ABCC7/CFTR (cystic fibrosis transmembrane conductance regulator). In the latter case, the goal is to rescue the function of the deficient transporters using various means, such as targeted pharmacotherapies and cell or gene therapy.

The aim of this Special Issue, “ABC Transporters in Human Diseases”, is to present, through original articles, reviews, and commentaries, the state-of-the-art of our current knowledge about the role of ABC transporters in human diseases and the proposed therapeutical options based on studies ranging from cell and animal models to patients. Topics may include, but are not limited to:

  • Phylogeny of ABC transporters and conservation through species
  • ABC transporters and multidrug resistance in cancer
  • Defective ABC transporters and human diseases
  • Regulation of the function of ABC transporters involved in multidrug resistance
  • Targeted therapies to rescue the function of defective ABC transporters
  • Cell and animal models for studying ABC transporters in health and disease
  • Structural insights into the molecular mechanisms of ABC-related diseases and the interaction of drug candidates with ABC transporters
  • Perspectives for diseases related with ABC transporter defects

Dr. Thomas Falguières
Guest Editor

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Keywords

  • ABC transporters
  • human diseases
  • targeted pharmacotherapy
  • drug candidates
  • animal models
  • cell models
  • structure

Published Papers (26 papers)

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Editorial

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5 pages, 417 KiB  
Editorial
ABC Transporters in Human Diseases: Future Directions and Therapeutic Perspectives
by Thomas Falguières
Int. J. Mol. Sci. 2022, 23(8), 4250; https://doi.org/10.3390/ijms23084250 - 12 Apr 2022
Cited by 2 | Viewed by 1597
Abstract
The goal of this Special Issue on “ABC Transporters in Human Diseases”, for which I was invited as a Guest Editor, was to provide an overview of the state-of-the-art research, understandings, and advances made in recent years on human diseases implicating ATP-binding cassette [...] Read more.
The goal of this Special Issue on “ABC Transporters in Human Diseases”, for which I was invited as a Guest Editor, was to provide an overview of the state-of-the-art research, understandings, and advances made in recent years on human diseases implicating ATP-binding cassette (ABC) transporters [...] Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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Research

Jump to: Editorial, Review

16 pages, 2145 KiB  
Article
The Reentry Helix Is Potentially Involved in Cholesterol Sensing of the ABCG1 Transporter Protein
by Zoltán Hegyi, Tamás Hegedűs and László Homolya
Int. J. Mol. Sci. 2022, 23(22), 13744; https://doi.org/10.3390/ijms232213744 - 08 Nov 2022
Cited by 1 | Viewed by 1000
Abstract
ABCG1 has been proposed to play a role in HDL-dependent cellular sterol regulation; however, details of the interaction between the transporter and its potential sterol substrates have not been revealed. In the present work, we explored the effect of numerous sterol compounds on [...] Read more.
ABCG1 has been proposed to play a role in HDL-dependent cellular sterol regulation; however, details of the interaction between the transporter and its potential sterol substrates have not been revealed. In the present work, we explored the effect of numerous sterol compounds on the two isoforms of ABCG1 and ABCG4 and made efforts to identify the molecular motifs in ABCG1 that are involved in the interaction with cholesterol. The functional readouts used include ABCG1-mediated ATPase activity and ABCG1-induced apoptosis. We found that both ABCG1 isoforms and ABCG4 interact with several sterol compounds; however, they have selective sensitivities to sterols. Mutational analysis of potential cholesterol-interacting motifs in ABCG1 revealed altered ABCG1 functions when F571, L626, or Y586 were mutated. L430A and Y660A substitutions had no functional consequence, whereas Y655A completely abolished the ABCG1-mediated functions. Detailed structural analysis of ABCG1 demonstrated that the mutations modulating ABCG1 functions are positioned either in the so-called reentry helix (G-loop/TM5b,c) (Y586) or in its close proximity (F571 and L626). Cholesterol molecules resolved in the structure of ABCG1 are also located close to Y586. Based on the experimental observations and structural considerations, we propose an essential role for the reentry helix in cholesterol sensing in ABCG1. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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16 pages, 3624 KiB  
Article
ABCB1 Does Not Require the Side-Chain Hydrogen-Bond Donors Gln347, Gln725, Gln990 to Confer Cellular Resistance to the Anticancer Drug Taxol
by Keerthana Sasitharan, Hamzah Asad Iqbal, Foteini Bifsa, Aleksandra Olszewska and Kenneth J. Linton
Int. J. Mol. Sci. 2021, 22(16), 8561; https://doi.org/10.3390/ijms22168561 - 09 Aug 2021
Cited by 5 | Viewed by 1686
Abstract
The multidrug efflux transporter ABCB1 is clinically important for drug absorption and distribution and can be a determinant of chemotherapy failure. Recent structure data shows that three glutamines donate hydrogen bonds to coordinate taxol in the drug binding pocket. This is consistent with [...] Read more.
The multidrug efflux transporter ABCB1 is clinically important for drug absorption and distribution and can be a determinant of chemotherapy failure. Recent structure data shows that three glutamines donate hydrogen bonds to coordinate taxol in the drug binding pocket. This is consistent with earlier drug structure-activity relationships that implicated the importance of hydrogen bonds in drug recognition by ABCB1. By replacing the glutamines with alanines we have tested whether any, or all, of Gln347, Gln725, and Gln990 are important for the transport of three different drug classes. Flow cytometric transport assays show that Q347A and Q990A act synergistically to reduce transport of Calcein-AM, BODIPY-verapamil, and OREGON GREEN-taxol bisacetate but the magnitude of the effect was dependent on the test drug and no combination of mutations completely abrogated function. Surprisingly, Q725A mutants generally improved transport of Calcein-AM and BODIPY-verapamil, suggesting that engagement of the wild-type Gln725 in a hydrogen bond is inhibitory for the transport mechanism. To test transport of unmodified taxol, stable expression of Q347/725A and the triple mutant was engineered and shown to confer equivalent resistance to the drug as the wild-type transporter, further indicating that none of these potential hydrogen bonds between transporter and transport substrate are critical for the function of ABCB1. The implications of the data for plasticity of the drug binding pocket are discussed. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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15 pages, 4137 KiB  
Article
RAB10 Interacts with ABCB4 and Regulates Its Intracellular Traffic
by Amel Ben Saad, Virginie Vauthier, Martine Lapalus, Elodie Mareux, Evangéline Bennana, Anne-Marie Durand-Schneider, Alix Bruneau, Jean-Louis Delaunay, Emmanuel Gonzales, Chantal Housset, Tounsia Aït-Slimane, François Guillonneau, Emmanuel Jacquemin and Thomas Falguières
Int. J. Mol. Sci. 2021, 22(13), 7087; https://doi.org/10.3390/ijms22137087 - 30 Jun 2021
Cited by 3 | Viewed by 2808
Abstract
ABCB4 (ATP-binding cassette subfamily B member 4) is an ABC transporter expressed at the canalicular membrane of hepatocytes where it ensures phosphatidylcholine secretion into bile. Genetic variations of ABCB4 are associated with several rare cholestatic diseases. The available treatments are not efficient for [...] Read more.
ABCB4 (ATP-binding cassette subfamily B member 4) is an ABC transporter expressed at the canalicular membrane of hepatocytes where it ensures phosphatidylcholine secretion into bile. Genetic variations of ABCB4 are associated with several rare cholestatic diseases. The available treatments are not efficient for a significant proportion of patients with ABCB4-related diseases and liver transplantation is often required. The development of novel therapies requires a deep understanding of the molecular mechanisms regulating ABCB4 expression, intracellular traffic, and function. Using an immunoprecipitation approach combined with mass spectrometry analyses, we have identified the small GTPase RAB10 as a novel molecular partner of ABCB4. Our results indicate that the overexpression of wild type RAB10 or its dominant-active mutant significantly increases the amount of ABCB4 at the plasma membrane expression and its phosphatidylcholine floppase function. Contrariwise, RAB10 silencing induces the intracellular retention of ABCB4 and then indirectly diminishes its secretory function. Taken together, our findings suggest that RAB10 regulates the plasma membrane targeting of ABCB4 and consequently its capacity to mediate phosphatidylcholine secretion. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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19 pages, 4884 KiB  
Article
Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model
by Flora Szeri, Valentina Corradi, Fatemeh Niaziorimi, Sylvia Donnelly, Gwenaëlle Conseil, Susan P. C. Cole, D. Peter Tieleman and Koen van de Wetering
Int. J. Mol. Sci. 2021, 22(13), 6910; https://doi.org/10.3390/ijms22136910 - 27 Jun 2021
Cited by 7 | Viewed by 1903
Abstract
Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization [...] Read more.
Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization inhibitor. Although ABCC6 is firmly linked to cellular ATP release, the molecular details of ABCC6-mediated ATP release remain elusive. Most of the currently available data support the hypothesis that ABCC6 is an ATP-dependent ATP efflux pump, an un-precedented function for an ABC transporter. This hypothesis implies the presence of an ATP-binding site in the substrate-binding cavity of ABCC6. We performed an extensive mutagenesis study using a new homology model based on recently published structures of its close homolog, bovine Abcc1, to characterize the substrate-binding cavity of ABCC6. Leukotriene C4 (LTC4), is a high-affinity substrate of ABCC1. We mutagenized fourteen amino acid residues in the rat ortholog of ABCC6, rAbcc6, that corresponded to the residues in ABCC1 found in the LTC4 binding cavity. Our functional characterization revealed that most of the amino acids in rAbcc6 corresponding to those found in the LTC4 binding pocket in bovine Abcc1 are not critical for ATP efflux. We conclude that the putative ATP binding site in the substrate-binding cavity of ABCC6/rAbcc6 is distinct from the bovine Abcc1 LTC4-binding site. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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16 pages, 4498 KiB  
Article
Analysis of Sequence Divergence in Mammalian ABCGs Predicts a Structural Network of Residues That Underlies Functional Divergence
by James I. Mitchell-White, Thomas Stockner, Nicholas Holliday, Stephen J. Briddon and Ian D. Kerr
Int. J. Mol. Sci. 2021, 22(6), 3012; https://doi.org/10.3390/ijms22063012 - 16 Mar 2021
Cited by 5 | Viewed by 2134
Abstract
The five members of the mammalian G subfamily of ATP-binding cassette transporters differ greatly in their substrate specificity. Four members of the subfamily are important in lipid transport and the wide substrate specificity of one of the members, ABCG2, is of significance due [...] Read more.
The five members of the mammalian G subfamily of ATP-binding cassette transporters differ greatly in their substrate specificity. Four members of the subfamily are important in lipid transport and the wide substrate specificity of one of the members, ABCG2, is of significance due to its role in multidrug resistance. To explore the origin of substrate selectivity in members 1, 2, 4, 5 and 8 of this subfamily, we have analysed the differences in conservation between members in a multiple sequence alignment of ABCG sequences from mammals. Mapping sets of residues with similar patterns of conservation onto the resolved 3D structure of ABCG2 reveals possible explanations for differences in function, via a connected network of residues from the cytoplasmic to transmembrane domains. In ABCG2, this network of residues may confer extra conformational flexibility, enabling it to transport a wider array of substrates. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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14 pages, 1690 KiB  
Article
Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout
by Yu Toyoda, Kateřina Pavelcová, Jana Bohatá, Pavel Ješina, Yu Kubota, Hiroshi Suzuki, Tappei Takada and Blanka Stiburkova
Int. J. Mol. Sci. 2021, 22(4), 1935; https://doi.org/10.3390/ijms22041935 - 16 Feb 2021
Cited by 16 | Viewed by 3180
Abstract
The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K—a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type—has been reportedly [...] Read more.
The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K—a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type—has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 μmol/L for men or 360 μmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397–405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations—c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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20 pages, 2480 KiB  
Article
New Evidence for P-gp-Mediated Export of Amyloid-β Peptides in Molecular, Blood-Brain Barrier and Neuronal Models
by Amanda B. Chai, Anika M. S. Hartz, Xuexin Gao, Alryel Yang, Richard Callaghan and Ingrid C. Gelissen
Int. J. Mol. Sci. 2021, 22(1), 246; https://doi.org/10.3390/ijms22010246 - 29 Dec 2020
Cited by 27 | Viewed by 3167
Abstract
Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. [...] Read more.
Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ40 and Aβ42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ42 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aβ40 and Aβ42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aβ out of the brain in Alzheimer’s disease. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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17 pages, 2502 KiB  
Article
Role of Genetic Variation in ABC Transporters in Breast Cancer Prognosis and Therapy Response
by Viktor Hlaváč, Radka Václavíková, Veronika Brynychová, Renata Koževnikovová, Katerina Kopečková, David Vrána, Jiří Gatěk and Pavel Souček
Int. J. Mol. Sci. 2020, 21(24), 9556; https://doi.org/10.3390/ijms21249556 - 15 Dec 2020
Cited by 14 | Viewed by 2427
Abstract
Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants [...] Read more.
Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants in coding and regulatory sequences of all human ABC genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 43 prioritized variants associating with response or survival in the above testing phase were then analyzed by allelic discrimination in the large validation set (n = 802). Variants in ABCA4, ABCA9, ABCA12, ABCB5, ABCC5, ABCC8, ABCC11, and ABCD4 associated with response and variants in ABCA7, ABCA13, ABCC4, and ABCG8 with survival of the patients. No association passed a false discovery rate test, however, the rs17822931 (Gly180Arg) in ABCC11, associating with response, and the synonymous rs17548783 in ABCA13 (survival) have a strong support in the literature and are, thus, interesting for further research. Although replicated associations have not reached robust statistical significance, the role of ABC transporters in breast cancer should not be ruled out. Future research and careful validation of findings will be essential for assessment of genetic variation which was not in the focus of this study, e.g., non-coding sequences, copy numbers, and structural variations together with somatic mutations. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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21 pages, 2534 KiB  
Article
5′ Untranslated Region Elements Show High Abundance and Great Variability in Homologous ABCA Subfamily Genes
by Pavel Dvorak, Viktor Hlavac and Pavel Soucek
Int. J. Mol. Sci. 2020, 21(22), 8878; https://doi.org/10.3390/ijms21228878 - 23 Nov 2020
Cited by 4 | Viewed by 2047
Abstract
The 12 members of the ABCA subfamily in humans are known for their ability to transport cholesterol and its derivatives, vitamins, and xenobiotics across biomembranes. Several ABCA genes are causatively linked to inborn diseases, and the role in cancer progression and metastasis is [...] Read more.
The 12 members of the ABCA subfamily in humans are known for their ability to transport cholesterol and its derivatives, vitamins, and xenobiotics across biomembranes. Several ABCA genes are causatively linked to inborn diseases, and the role in cancer progression and metastasis is studied intensively. The regulation of translation initiation is implicated as the major mechanism in the processes of post-transcriptional modifications determining final protein levels. In the current bioinformatics study, we mapped the features of the 5′ untranslated regions (5′UTR) known to have the potential to regulate translation, such as the length of 5′UTRs, upstream ATG codons, upstream open-reading frames, introns, RNA G-quadruplex-forming sequences, stem loops, and Kozak consensus motifs, in the DNA sequences of all members of the subfamily. Subsequently, the conservation of the features, correlations among them, ribosome profiling data as well as protein levels in normal human tissues were examined. The 5′UTRs of ABCA genes contain above-average numbers of upstream ATGs, open-reading frames and introns, as well as conserved ones, and these elements probably play important biological roles in this subfamily, unlike RG4s. Although we found significant correlations among the features, we did not find any correlation between the numbers of 5′UTR features and protein tissue distribution and expression scores. We showed the existence of single nucleotide variants in relation to the 5′UTR features experimentally in a cohort of 105 breast cancer patients. 5′UTR features presumably prepare a complex playground, in which the other elements such as RNA binding proteins and non-coding RNAs play the major role in the fine-tuning of protein expression. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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20 pages, 3265 KiB  
Article
Transmembrane Polar Relay Drives the Allosteric Regulation for ABCG5/G8 Sterol Transporter
by Bala M. Xavier, Aiman A. Zein, Angelica Venes, Junmei Wang and Jyh-Yeuan Lee
Int. J. Mol. Sci. 2020, 21(22), 8747; https://doi.org/10.3390/ijms21228747 - 19 Nov 2020
Cited by 7 | Viewed by 2525
Abstract
The heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the biliary and transintestinal secretion of cholesterol and dietary plant sterols. Missense mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis. A new molecular [...] Read more.
The heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the biliary and transintestinal secretion of cholesterol and dietary plant sterols. Missense mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis. A new molecular framework was recently established by a crystal structure of human ABCG5/G8 and reveals a network of polar and charged amino acids in the core of the transmembrane domains, namely, a polar relay. In this study, we utilize genetic variants to dissect the mechanistic role of this transmembrane polar relay in controlling ABCG5/G8 function. We demonstrated a sterol-coupled ATPase activity of ABCG5/G8 by cholesteryl hemisuccinate (CHS), a relatively water-soluble cholesterol memetic, and characterized CHS-coupled ATPase activity of three loss-of-function missense variants, R543S, E146Q, and A540F, which are respectively within, in contact with, and distant from the polar relay. The results established an in vitro phenotype of the loss-of-function and missense mutations of ABCG5/G8, showing significantly impaired ATPase activity and loss of energy sufficient to weaken the signal transmission from the transmembrane domains. Our data provide a biochemical evidence underlying the importance of the polar relay and its network in regulating the catalytic activity of ABCG5/G8 sterol transporter. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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16 pages, 2587 KiB  
Article
Brain Distribution of Dual ABCB1/ABCG2 Substrates Is Unaltered in a Beta-Amyloidosis Mouse Model
by Thomas Wanek, Viktoria Zoufal, Mirjam Brackhan, Markus Krohn, Severin Mairinger, Thomas Filip, Michael Sauberer, Johann Stanek, Thomas Pekar, Jens Pahnke and Oliver Langer
Int. J. Mol. Sci. 2020, 21(21), 8245; https://doi.org/10.3390/ijms21218245 - 03 Nov 2020
Cited by 5 | Viewed by 2044
Abstract
Background: ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) are co-localized at the blood-brain barrier (BBB), where they restrict the brain distribution of many different drugs. Moreover, ABCB1 and possibly ABCG2 play a role in Alzheimer’s disease (AD) by mediating the brain clearance [...] Read more.
Background: ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) are co-localized at the blood-brain barrier (BBB), where they restrict the brain distribution of many different drugs. Moreover, ABCB1 and possibly ABCG2 play a role in Alzheimer’s disease (AD) by mediating the brain clearance of beta-amyloid (Aβ) across the BBB. This study aimed to compare the abundance and activity of ABCG2 in a commonly used β-amyloidosis mouse model (APP/PS1-21) with age-matched wild-type mice. Methods: The abundance of ABCG2 was assessed by semi-quantitative immunohistochemical analysis of brain slices of APP/PS1-21 and wild-type mice aged 6 months. Moreover, the brain distribution of two dual ABCB1/ABCG2 substrate radiotracers ([11C]tariquidar and [11C]erlotinib) was assessed in APP/PS1-21 and wild-type mice with positron emission tomography (PET). [11C]Tariquidar PET scans were performed without and with partial inhibition of ABCG2 with Ko143, while [11C]erlotinib PET scans were only performed under baseline conditions. Results: Immunohistochemical analysis revealed a significant reduction (by 29–37%) in the number of ABCG2-stained microvessels in the brains of APP/PS1-21 mice. Partial ABCG2 inhibition significantly increased the brain distribution of [11C]tariquidar in APP/PS1-21 and wild-type mice, but the brain distribution of [11C]tariquidar did not differ under both conditions between the two mouse strains. Similar results were obtained with [11C]erlotinib. Conclusions: Despite a reduction in the abundance of cerebral ABCG2 and ABCB1 in APP/PS1-21 mice, the brain distribution of two dual ABCB1/ABCG2 substrates was unaltered. Our results suggest that the brain distribution of clinically used ABCB1/ABCG2 substrate drugs may not differ between AD patients and healthy people. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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21 pages, 3732 KiB  
Article
Roles of ABCC1 and ABCC4 in Proliferation and Migration of Breast Cancer Cell Lines
by Floren G. Low, Kiran Shabir, James E. Brown, Roslyn M. Bill and Alice J. Rothnie
Int. J. Mol. Sci. 2020, 21(20), 7664; https://doi.org/10.3390/ijms21207664 - 16 Oct 2020
Cited by 20 | Viewed by 3052
Abstract
ABCC1 and ABCC4 utilize energy from ATP hydrolysis to transport many different molecules, including drugs, out of the cell and, as such, have been implicated in causing drug resistance. However recently, because of their ability to transport signaling molecules and inflammatory mediators, it [...] Read more.
ABCC1 and ABCC4 utilize energy from ATP hydrolysis to transport many different molecules, including drugs, out of the cell and, as such, have been implicated in causing drug resistance. However recently, because of their ability to transport signaling molecules and inflammatory mediators, it has been proposed that ABCC1 and ABCC4 may play a role in the hallmarks of cancer development and progression, independent of their drug efflux capabilities. Breast cancer is the most common cancer affecting women. In this study, the aim was to investigate whether ABCC1 or ABCC4 play a role in the proliferation or migration of breast cancer cell lines MCF-7 (luminal-type, receptor-positive) and MDA-MB-231 (basal-type, triple-negative). The effects of small molecule inhibitors or siRNA-mediated knockdown of ABCC1 or ABCCC4 were measured. Colony formation assays were used to assess the clonogenic capacity, MTT assays to measure the proliferation, and scratch assays and Transwell assays to monitor the cellular migration. The results showed a role for ABCC1 in cellular proliferation, whilst ABCC4 appeared to be more important for cellular migration. ELISA studies implicated cAMP and/or sphingosine-1-phosphate efflux in the mechanism by which these transporters mediate their effects. However, this needs to be investigated further, as it is key to understand the mechanisms before they can be considered as targets for treatment. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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22 pages, 5722 KiB  
Article
Full Rescue of F508del-CFTR Processing and Function by CFTR Modulators Can Be Achieved by Removal of Two Regulatory Regions
by Inna Uliyakina, Hugo M. Botelho, Ana C. da Paula, Sara Afonso, Miguel J. Lobo, Verónica Felício, Carlos M. Farinha and Margarida D. Amaral
Int. J. Mol. Sci. 2020, 21(12), 4524; https://doi.org/10.3390/ijms21124524 - 25 Jun 2020
Cited by 7 | Viewed by 2200
Abstract
Cystic Fibrosis (CF) is caused by mutations in the CF Transmembrane conductance Regulator (CFTR), the only ATP-binding cassette (ABC) transporter functioning as a channel. Unique to CFTR is a regulatory domain which includes a highly conformationally dynamic region—the regulatory extension (RE). The first [...] Read more.
Cystic Fibrosis (CF) is caused by mutations in the CF Transmembrane conductance Regulator (CFTR), the only ATP-binding cassette (ABC) transporter functioning as a channel. Unique to CFTR is a regulatory domain which includes a highly conformationally dynamic region—the regulatory extension (RE). The first nucleotide-binding domain of CFTR contains another dynamic region—regulatory insertion (RI). Removal of RI rescues the trafficking defect of CFTR with F508del, the most common CF-causing mutation. Here we aimed to assess the impact of RE removal (with/without RI or genetic revertants) on F508del-CFTR trafficking and how CFTR modulator drugs VX-809/lumacaftor and VX-770/ivacaftor rescue these variants. We generated cell lines expressing ΔRE and ΔRI CFTR (with/without genetic revertants) and assessed CFTR expression, stability, plasma membrane levels, and channel activity. Our data demonstrated that ΔRI significantly enhanced rescue of F508del-CFTR by VX-809. While the presence of the RI seems to be precluding full rescue of F508del-CFTR processing by VX-809, this region appears essential to rescue its function by VX-770, suggesting some contradictory role in rescue of F508del-CFTR by these two modulators. This negative impact of RI removal on VX-770-stimulated currents on F508del-CFTR can be compensated by deletion of the RE which also leads to the stabilization of this mutant. Despite both regions being conformationally dynamic, RI precludes F508del-CFTR processing while RE affects mostly its stability and channel opening. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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Review

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13 pages, 712 KiB  
Review
The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update
by Robert Eckenstaler and Ralf A. Benndorf
Int. J. Mol. Sci. 2021, 22(13), 6678; https://doi.org/10.3390/ijms22136678 - 22 Jun 2021
Cited by 40 | Viewed by 4784
Abstract
Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority [...] Read more.
Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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22 pages, 1986 KiB  
Review
Peroxisomal ABC Transporters: An Update
by Ali Tawbeh, Catherine Gondcaille, Doriane Trompier and Stéphane Savary
Int. J. Mol. Sci. 2021, 22(11), 6093; https://doi.org/10.3390/ijms22116093 - 05 Jun 2021
Cited by 24 | Viewed by 5698
Abstract
ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). [...] Read more.
ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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31 pages, 3321 KiB  
Review
Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms
by Narakorn Khunweeraphong and Karl Kuchler
Int. J. Mol. Sci. 2021, 22(9), 4806; https://doi.org/10.3390/ijms22094806 - 30 Apr 2021
Cited by 22 | Viewed by 4370
Abstract
Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter [...] Read more.
Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter members, ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) appear to act as brothers in arms in promoting or causing MDR in a variety of therapeutic cancer settings. However, their molecular mechanisms of action, the basis for their broad and overlapping substrate selectivity, remains ill-posed. The rapidly increasing numbers of high-resolution atomic structures from X-ray crystallography or cryo-EM of mammalian ABC multidrug transporters initiated a new era towards a better understanding of structure–function relationships, and for the dynamics and mechanisms driving their transport cycles. In addition, the atomic structures offered new evolutionary perspectives in cases where transport systems have been structurally conserved from bacteria to humans, including the pleiotropic drug resistance (PDR) family in fungal pathogens for which high resolution structures are as yet unavailable. In this review, we will focus the discussion on comparative mechanisms of mammalian ABCG and fungal PDR transporters, owing to their close evolutionary relationships. In fact, the atomic structures of ABCG2 offer excellent models for a better understanding of fungal PDR transporters. Based on comparative structural models of ABCG transporters and fungal PDRs, we propose closely related or even conserved catalytic cycles, thus offering new therapeutic perspectives for preventing MDR in infectious disease settings. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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15 pages, 12465 KiB  
Review
Role of ABCA7 in Human Health and in Alzheimer’s Disease
by Shiraz Dib, Jens Pahnke and Fabien Gosselet
Int. J. Mol. Sci. 2021, 22(9), 4603; https://doi.org/10.3390/ijms22094603 - 27 Apr 2021
Cited by 35 | Viewed by 5271
Abstract
Several studies, including genome wide association studies (GWAS), have strongly suggested a central role for the ATP-binding cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD). This ABC transporter is now considered as an important genetic determinant for late onset Alzheimer [...] Read more.
Several studies, including genome wide association studies (GWAS), have strongly suggested a central role for the ATP-binding cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD). This ABC transporter is now considered as an important genetic determinant for late onset Alzheimer disease (LOAD) by regulating several molecular processes such as cholesterol metabolism and amyloid processing and clearance. In this review we shed light on these new functions and their cross-talk, explaining its implication in brain functioning, and therefore in AD onset and development. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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29 pages, 1478 KiB  
Review
ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions
by Briana K. Shimada, Viola Pomozi, Janna Zoll, Sheree Kuo, Ludovic Martin and Olivier Le Saux
Int. J. Mol. Sci. 2021, 22(9), 4555; https://doi.org/10.3390/ijms22094555 - 27 Apr 2021
Cited by 21 | Viewed by 4802
Abstract
Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization [...] Read more.
Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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12 pages, 3365 KiB  
Review
Structural and Functional Characterization of the ABCC6 Transporter in Hepatic Cells: Role on PXE, Cancer Therapy and Drug Resistance
by Faustino Bisaccia, Prashant Koshal, Vittorio Abruzzese, Maria Antonietta Castiglione Morelli and Angela Ostuni
Int. J. Mol. Sci. 2021, 22(6), 2858; https://doi.org/10.3390/ijms22062858 - 11 Mar 2021
Cited by 9 | Viewed by 3473
Abstract
Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of [...] Read more.
Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of ABCC6 in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as NT5E and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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30 pages, 839 KiB  
Review
Medically Important Alterations in Transport Function and Trafficking of ABCG2
by László Homolya
Int. J. Mol. Sci. 2021, 22(6), 2786; https://doi.org/10.3390/ijms22062786 - 10 Mar 2021
Cited by 16 | Viewed by 2844
Abstract
Several polymorphisms and mutations in the human ABCG2 multidrug transporter result in reduced plasma membrane expression and/or diminished transport function. Since ABCG2 plays a pivotal role in uric acid clearance, its malfunction may lead to hyperuricemia and gout. On the other hand, ABCG2 [...] Read more.
Several polymorphisms and mutations in the human ABCG2 multidrug transporter result in reduced plasma membrane expression and/or diminished transport function. Since ABCG2 plays a pivotal role in uric acid clearance, its malfunction may lead to hyperuricemia and gout. On the other hand, ABCG2 residing in various barrier tissues is involved in the innate defense mechanisms of the body; thus, genetic alterations in ABCG2 may modify the absorption, distribution, excretion of potentially toxic endo- and exogenous substances. In turn, this can lead either to altered therapy responses or to drug-related toxic reactions. This paper reviews the various types of mutations and polymorphisms in ABCG2, as well as the ways how altered cellular processing, trafficking, and transport activity of the protein can contribute to phenotypic manifestations. In addition, the various methods used for the identification of the impairments in ABCG2 variants and the different approaches to correct these defects are overviewed. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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15 pages, 842 KiB  
Review
Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8
by Kori Williams, Allison Segard and Gregory A. Graf
Int. J. Mol. Sci. 2021, 22(5), 2641; https://doi.org/10.3390/ijms22052641 - 05 Mar 2021
Cited by 23 | Viewed by 3931
Abstract
Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to [...] Read more.
Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty years since its discovery. The genomic era has revealed that there are far more carriers of loss of function mutations and likely pathogenic variants of ABCG5 ABCG8 than previously thought. The impact of these variants on G5G8 structure and activity are largely unknown. We propose a classification system for ABCG5 ABCG8 mutants based on previously published systems for diseases caused by defects in ABC transporters. This system establishes a framework for the comprehensive analysis of disease-associated variants and their impact on G5G8 structure–function. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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17 pages, 636 KiB  
Review
Molecular Regulation of Canalicular ABC Transporters
by Amel Ben Saad, Alix Bruneau, Elodie Mareux, Martine Lapalus, Jean-Louis Delaunay, Emmanuel Gonzales, Emmanuel Jacquemin, Tounsia Aït-Slimane and Thomas Falguières
Int. J. Mol. Sci. 2021, 22(4), 2113; https://doi.org/10.3390/ijms22042113 - 20 Feb 2021
Cited by 14 | Viewed by 3398
Abstract
The ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of hepatocytes mediate the secretion of several compounds into the bile canaliculi and therefore play a key role in bile secretion. Among these transporters, ABCB11 secretes bile acids, ABCB4 translocates phosphatidylcholine and ABCG5/G8 [...] Read more.
The ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of hepatocytes mediate the secretion of several compounds into the bile canaliculi and therefore play a key role in bile secretion. Among these transporters, ABCB11 secretes bile acids, ABCB4 translocates phosphatidylcholine and ABCG5/G8 is responsible for cholesterol secretion, while ABCB1 and ABCC2 transport a variety of drugs and other compounds. The dysfunction of these transporters leads to severe, rare, evolutionary biliary diseases. The development of new therapies for patients with these diseases requires a deep understanding of the biology of these transporters. In this review, we report the current knowledge regarding the regulation of canalicular ABC transporters’ folding, trafficking, membrane stability and function, and we highlight the role of molecular partners in these regulating mechanisms. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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30 pages, 1560 KiB  
Review
The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease
by Leonor Jacobo-Albavera, Mayra Domínguez-Pérez, Diana Jhoseline Medina-Leyte, Antonia González-Garrido and Teresa Villarreal-Molina
Int. J. Mol. Sci. 2021, 22(4), 1593; https://doi.org/10.3390/ijms22041593 - 05 Feb 2021
Cited by 71 | Viewed by 9692
Abstract
Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular [...] Read more.
Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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22 pages, 1592 KiB  
Review
The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies
by Muhammad Imran Sohail, Yaprak Dönmez-Cakil, Dániel Szöllősi, Thomas Stockner and Peter Chiba
Int. J. Mol. Sci. 2021, 22(2), 784; https://doi.org/10.3390/ijms22020784 - 14 Jan 2021
Cited by 15 | Viewed by 4799
Abstract
The bile salt export pump (BSEP/ABCB11) is responsible for the transport of bile salts from hepatocytes into bile canaliculi. Malfunction of this transporter results in progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2) and intrahepatic cholestasis of [...] Read more.
The bile salt export pump (BSEP/ABCB11) is responsible for the transport of bile salts from hepatocytes into bile canaliculi. Malfunction of this transporter results in progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2) and intrahepatic cholestasis of pregnancy (ICP). Over the past few years, several small molecular weight compounds have been identified, which hold the potential to treat these genetic diseases (chaperones and potentiators). As the treatment response is mutation-specific, genetic analysis of the patients and their families is required. Furthermore, some of the mutations are refractory to therapy, with the only remaining treatment option being liver transplantation. In this review, we will focus on the molecular structure of ABCB11, reported mutations involved in cholestasis and current treatment options for inherited BSEP deficiencies. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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13 pages, 305 KiB  
Review
Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects
by Piter J. Bosma, Marius Wits and Ronald P. J. Oude-Elferink
Int. J. Mol. Sci. 2021, 22(1), 273; https://doi.org/10.3390/ijms22010273 - 29 Dec 2020
Cited by 15 | Viewed by 3075
Abstract
Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) [...] Read more.
Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) in type 2; ABCB4 (phosphatidylcholine floppase) in type 3. In addition, ABCB11 function is affected in 3 other types of PFIC. A lack of effective treatment makes a liver transplantation necessary in most patients. In view of long-term adverse effects, for instance due to life-long immune suppression needed to prevent organ rejection, gene therapy could be a preferable approach, as supported by proof of concept in animal models for PFIC3. This review discusses the feasibility of gene therapy as an alternative for liver transplantation for all forms of PFIC based on their pathological mechanism. Conclusion: Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality. Full article
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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