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Structural analogues of roscovitine rescue the intracellular traffic and the function of ER-retained ABCB4 variants in cell models
- Source :
- Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019), Scientific Reports
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Adenosine triphosphate binding cassette transporter, subfamily B member 4 (ABCB4) is the transporter of phosphatidylcholine at the canalicular membrane of hepatocytes. ABCB4 deficiency, due to genetic variations, is responsible for progressive familial intrahepatic cholestasis type 3 (PFIC3) and other rare biliary diseases. Roscovitine is a molecule in clinical trial that was shown to correct the F508del variant of cystic fibrosis transmembrane conductance regulator (CFTR), another ABC transporter. In the present study, we hypothesized that roscovitine could act as a corrector of ABCB4 traffic-defective variants. Using HEK and HepG2 cells, we showed that roscovitine corrected the traffic and localisation at the plasma membrane of ABCB4-I541F, a prototypical intracellularly retained variant. However, roscovitine caused cytotoxicity, which urged us to synthesize non-toxic structural analogues. Roscovitine analogues were able to correct the intracellular traffic of ABCB4-I541F in HepG2 cells. Importantly, the phospholipid secretion activity of this variant was substantially rescued by three analogues (MRT2-235, MRT2-237 and MRT2-243) in HEK cells. We showed that these analogues also triggered the rescue of intracellular traffic and function of two other intracellularly retained ABCB4 variants, i.e. I490T and L556R. Our results indicate that structural analogues of roscovitine can rescue genetic variations altering the intracellular traffic of ABCB4 and should be considered as therapeutic means for severe biliary diseases caused by this class of variations.
- Subjects :
- 0301 basic medicine
ATP Binding Cassette Transporter, Subfamily B
Cell Survival
Fluorescent Antibody Technique
lcsh:Medicine
Antineoplastic Agents
ATP-binding cassette transporter
Endoplasmic Reticulum
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
Roscovitine
Humans
Secretion
lcsh:Science
Protein Kinase Inhibitors
Liver diseases
Multidisciplinary
Dose-Response Relationship, Drug
Molecular Structure
Protein transport
biology
Chemistry
lcsh:R
HEK 293 cells
Transporter
ABCB4
Cystic fibrosis transmembrane conductance regulator
3. Good health
Cell biology
030104 developmental biology
biology.protein
Mutant Proteins
lcsh:Q
Adenosine triphosphate
030217 neurology & neurosurgery
Intracellular
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....9b6d2c91321b976602dffd674b864ff8