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Characterization of a newly identified polymorphic variant (M71V) of ABCG2 multidrug transporter
Author(s) -
Homolya Laszlo,
Bartos Zsuzsa,
Zambo Boglarka,
Mozner Orsolya,
Sarkadi Balazs
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.462.2
Subject(s) - abcg2 , transporter , atp binding cassette transporter , biology , in silico , microbiology and biotechnology , intracellular , efflux , cell , pharmacology , computational biology , gene , genetics
The ABCG2 is a membrane transporter protein, which expels endo‐ and xenobiotics from the cells. Since its overexpression in tumor cells can confer resistance to multiple drugs, ABCG2 is also known as a multidrug transporter. Uric acid is one of the relevant transported physiological substrates of ABCG2, thus, dysfunction of this transporter can lead to hyperuricaemia or gout. In a previous work, using expression level screening in red blood cells from hyperuricaemic patients and normal subjects, a new polymorphic variant (M71V) of ABCG2 has been identified. Our recent study focuses on the cell biological characterization of the ABCG2‐M71V variant, investigating its expression, transport properties, localization, and cellular trafficking in comparison with that of the wild type and the gout‐associated Q141K ABCG2 variants. In addition to classical biochemical approaches, we applied advanced cell biological method to follow the dynamics of cellular routing of the ABCG2 variants. Our result demonstrated that ABCG2‐M71V has a trafficking defect, exhibits predominant intracellular localization and shows lower expression level, but its transport function remained mainly preserved. Treatment of the cells with pharmacological chaperons, such as 4‐phenyl butyrate and colchicine, can enhance the delivery of this ABCG2 variant to the cell surface. In summary, our results imply that the M71V substitution in the ABCG2 transporter may result in an unstable protein, which gets partially degraded; however, rescuing this ABCG2 variant from degradation by pharmacological chaperons can recover the impaired functionality caused by this polymorphism. Support or Funding Information This research has been supported by the National Research, Development and Innovation Fund (Hungary) (grant numbers: OTKA_K 115375 to B.S., OTKA_K 128123 to L.H., and FIEK_16‐1‐2016‐0005 to L.H. and B.S.), as well as by the Momentum Program of the Hungarian Academy of Sciences (LP2012‐025). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .