An inventory of lysosomal ABC transporters

Abele, Rupert

doi:10.1002/1873-3468.13967

Cited by 36 publications

(33 citation statements)

References 157 publications

(219 reference statements)

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“…Unlike other ABCD transporters, ABCD4 is not found in peroxisomes, but in lysosomes. It takes part in transport of cobalamin (vitamin B12) and mutations in this transporter cause inherited defects of intracellular cobalamin metabolism [ 10 ]. Low transcript levels of this gene were also associated with shorter DFS of colorectal cancer patients [ 20 ] and ABCD4 was among amplified genes in resistant cancer cell lines [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Family C is mostly dedicated to multidrug resistance (MRP1-6) [ 8 , 9 ], but ABCC6, ABCC7, and ABCC8/9 are linked to serious diseases (pseudoxanthoma elasticum, cystic fibrosis, and diabetes mellitus, respectively) [ 9 ]. ABCDs are responsible for transport of fatty acids from peroxisomes to the cytoplasm [ 10 ] and ABCGs transport various products of metabolism, xenobiotics including anti-cancer drugs, bile acids, and steroids [ 11 ]. The rest of the transporters are not involved in transport, but rather act as translational inhibitors or protein synthesis regulators (ABCFs and ABCEs) [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Role of Genetic Variation in ABC Transporters in Breast Cancer Prognosis and Therapy Response

Hlaváč

Václavíková

Brynychová

et al. 2020

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Genetic Variation in ABC Transporters in Breast Cancer Prognosis and Therapy Response

Hlaváč

Václavíková

Brynychová

et al. 2020

IJMS

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“…They are multidomain multispanning membrane proteins that hydrolyze ATP to transport a variety of substrates (from nutrients, metabolites, vitamins, drugs, and lipids, to trace metals and small ions) across membranes. Their defects often cause disease [4]. All ABC transporters have a similar domain architecture with at least two transmembrane domains (TMDs) and two cytoplasmic nucleotide-binding domains (NBDs) [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Co-translational folding of the first transmembrane domain of ABC-transporter CFTR is supported by assembly with the first cytosolic domain

Kleizen

Willigen

Mijnders

et al. 2020

Preprint

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ABC-transporters transport a wealth of molecules across membranes and consist of transmembrane and cytosolic domains. Their activity cycle involves a tightly regulated and concerted domain choreography, with regulation driven by the cytosolic domains, and function by the transmembrane domains. Folding of these polytopic multidomain proteins to their functional state is a challenge for cells, which is mitigated by co-translational and sequential events. We here reveal the first stages of co-translational domain folding and assembly of CFTR, the protein defective in the most abundant rare inherited disease cystic fibrosis, by combining biosynthetic radiolabeling with protease-susceptibility assays and domain-specific antibodies. The most N-terminal domain, TMD1 (transmembrane domain 1), folds both its hydrophobic and soluble helices during translation: the transmembrane helices pack tightly and the cytosolic N- and C-termini assemble with the first cytosolic helical loop ICL1, leaving only ICL2 exposed. This N-C-ICL1 assembly is strengthened by two independent events: i) assembly of ICL1 with the N-terminal subdomain of the next domain, cytosolic NBD1 (nucleotide-binding domain 1); and ii) in the presence of corrector drug VX-809, which rescues cell-surface expression of a range of disease-causing CFTR mutants. Both lead to increased shielding of the CFTR N-terminus, and their additivity implies a different mode of action. Early assembly of NBD1 and TMD1 is essential for CFTR folding and positions both domains for the required assembly with TMD2. Altogether, we have gained insights into this first, nucleating, VX-809-enhanced domain-assembly event during and immediately after CFTR translation, involving structures conserved in type-I ABC exporters.

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“…In the lysosomes, doxorubicin was colocalized with Pgp-EGFP, indicating that Pgp, at least in part, mediated the lysosomal sequestration of doxorubicin as recently reported for hCMEC/D3- MDR1 -EGFP cells [ 13 ] and cancer cells [ 59 ]. As described in the Introduction, cytostatic agents enter the lysosome either by passive diffusion along the pH gradient or may be actively transported across the membrane by inward-turned Pgp embedded in the lysosomal membrane [ 11 , 12 ], although the latter mechanism is debated [ 51 , 60 ]. The fate of drugs sequestered in lysosomes remains to be elucidated in more detail, but it was suggested that they either stay trapped in lysosomes, are degraded in the lysosomes, or are eliminated from the cell by drug-induced lysosomal exocytosis, preventing lysosomal damage [ 9 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

Similarities and differences in the localization, trafficking, and function of P-glycoprotein in MDR1-EGFP-transduced rat versus human brain capillary endothelial cell lines

Gericke¹,

Borsdorf²,

Wienböker³

et al. 2021

Fluids Barriers CNS

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Background In vitro models based on brain capillary endothelial cells (BCECs) are among the most versatile tools in blood–brain barrier research for testing drug penetration into the brain and how this is affected by efflux transporters such as P-glycoprotein (Pgp). However, compared to freshly isolated brain capillaries or primary BCECs, the expression of Pgp in immortalized BCEC lines is markedly lower, which prompted us previously to transduce the widely used human BCEC line hCMEC/D3 with a doxycycline-inducible MDR1-EGFP fusion plasmid. The EGFP-labeled Pgp in these cells allows studying the localization and trafficking of the transporter and how these processes are affected by drug exposure. Here we used this strategy for the rat BCEC line RBE4 and performed a face-to-face comparison of RBE4 and hCMEC/D3 wild-type (WT) and MDR1-EGFP transduced cells. Methods MDR1-EGFP-transduced variants were derived from WT cells by lentiviral transduction, using an MDR1-linker-EGFP vector. Localization, trafficking, and function of Pgp were compared in WT and MDR1-EGFP transduced cell lines. Primary cultures of rat BCECs and freshly isolated rat brain capillaries were used for comparison. Results All cells exhibited typical BCEC morphology. However, significant differences were observed in the localization of Pgp in that RBE4-MDR1-EGFP cells expressed Pgp primarily at the plasma membrane, whereas in hCMEC/D3 cells, the Pgp-EGFP fusion protein was visible both at the plasma membrane and in endolysosomal vesicles. Exposure to doxorubicin increased the number of Pgp-EGFP-positive endolysosomes, indicating a lysosomotropic effect. Furthermore, lysosomal trapping of doxorubicin was observed, likely contributing to the protection of the cell nucleus from damage. In cocultures of WT and MDR1-EGFP transduced cells, intercellular Pgp-EGFP trafficking was observed in RBE4 cells as previously reported for hCMEC/D3 cells. Compared to WT cells, the MDR1-EGFP transduced cells exhibited a significantly higher expression and function of Pgp. However, the junctional tightness of WT and MDR1-EGFP transduced RBE4 and hCMEC/D3 cells was markedly lower than that of primary BCECs, excluding the use of the cell lines for studying vectorial drug transport. Conclusions The present data indicate that MDR1-EGFP transduced RBE4 cells are an interesting tool to study the biogenesis of lysosomes and Pgp-mediated lysosomal drug trapping in response to chemotherapeutic agents and other compounds at the level of the blood–brain barrier.

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An inventory of lysosomal ABC transporters

Cited by 36 publications

References 157 publications

Role of Genetic Variation in ABC Transporters in Breast Cancer Prognosis and Therapy Response

Role of Genetic Variation in ABC Transporters in Breast Cancer Prognosis and Therapy Response

Co-translational folding of the first transmembrane domain of ABC-transporter CFTR is supported by assembly with the first cytosolic domain

Similarities and differences in the localization, trafficking, and function of P-glycoprotein in MDR1-EGFP-transduced rat versus human brain capillary endothelial cell lines

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