Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter

Boglárka Zámbó,Zsuzsa Bartos,Ágnes Telbisz,Tamás I Orbán,György Török,Balázs Sarkadi,György Várady,Orsolya Mózner,László Homolya

doi:10.1007/s00018-019-03186-2

Abstract

The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics; thus the relatively frequent polymorphic and mutant ABCG2 variants in the population may significantly alter disease conditions and pharmacological effects. Low-level or non-functional ABCG2 expression may increase individual drug toxicity, reduce cancer drug resistance, and result in hyperuricemia and gout. In the present work we have studied the cellular expression, trafficking, and function of nine naturally occurring polymorphic and mutant variants of ABCG2. A comprehensive analysis of the membrane localization, transport, and ATPase activity, as well as retention and degradation in intracellular compartments was performed. Among the examined variants, R147W and R383C showed expression and/or protein folding defects, indicating that they could indeed contribute to ABCG2 functional deficiency. These studies and the applied methods should significantly promote the exploration of the medical effects of these personal variants, promote potential therapies, and help to elucidate the specific role of the affected regions in the folding and function of the ABCG2 protein.

Highlights

The human ABCG2 belongs to the ABC superfamily and is responsible for the transfer of wide variety of endogenous substances through the plasma membrane [1, 2]
We found that the total expression levels of the K360Δ, F373C, T434M, and S476P ABCG2 variants were similar to that of the wild-type protein, the variants M71V, Q141K, and T153M had lower but well measurable expression, while the R147W and R383C variants showed no measurable expression in this system
Mutations or single nucleotide polymorphisms (SNP) in the ABCG2 gene may influence the transport of these substrates, leading to pathological alterations in the human body

Summary

Introduction

The human ABCG2 belongs to the ABC superfamily and is responsible for the transfer of wide variety of endogenous substances through the plasma membrane [1, 2]. ABCG2 is present in the GI tract [3, 4], the blood–brain barrier [5], the placenta [6], and in various stem cells [7]. This transporter protein is very important for the absorption, distribution, Boglárka Zámbó and Orsolya Mózner contributed to this work. There is growing evidence that the reduced level and/or function of ABCG2 contribute to the development of the painful disease, gout. It has been established that numerous missense mutations in the ABCG2 gene are present in the human population [18,19,20], and some of these mutations may lead to reduced function and/ or expression of the protein

Methods

Results

Conclusion