Cellular Processing of the ABCG2 Transporter-Potential Effects on Gout and Drug Metabolism.

Orsolya Mózner,László Homolya,Balázs Sarkadi,Boglárka Zámbó,Zsuzsa Bartos,Tamás Hegedűs

doi:10.3390/cells8101215

Abstract

The human ABCG2 is an important plasma membrane multidrug transporter, involved in uric acid secretion, modulation of absorption of drugs, and in drug resistance of cancer cells. Variants of the ABCG2 transporter, affecting cellular processing and trafficking, have been shown to cause gout and increased drug toxicity. In this paper, we overview the key cellular pathways involved in the processing and trafficking of large membrane proteins, focusing on ABC transporters. We discuss the information available for disease-causing polymorphic variants and selected mutations of ABCG2, causing increased degradation and impaired travelling of the transporter to the plasma membrane. In addition, we provide a detailed in silico analysis of an as yet unrecognized loop region of the ABCG2 protein, in which a recently discovered mutation may actually promote ABCG2 membrane expression. We suggest that post-translational modifications in this unstructured loop at the cytoplasmic surface of the protein may have special influence on ABCG2 processing and trafficking.

Highlights

ABCG2 is a key protein in the extrusion of endo- and xenobiotics from numerous cell types and was shown to be involved in uric acid secretion, the modulation of drug absorption [28], as well as in the drug resistance of cancer cells [29]
In addition to potential transcriptional and processing regulatory effects, in this paper we focus on the potential role of the hereditary genetic variants of ABCG2
We provide an overview and structural modeling for the disease-related polymorphic and mutant ABCG2 variants, focusing on the in silico analysis of a specific loop region with an as yet unresolved structure

Summary

Regulation of Folding and Trafficking of the ABCG2 Multidrug Transporter

ABCG2 is a key protein in the extrusion of endo- and xenobiotics from numerous cell types and was shown to be involved in uric acid secretion, the modulation of drug absorption [28], as well as in the drug resistance of cancer cells [29]. The ABCG2 protein function is only slightly affected by the mutation, but due to improper folding, they have a reduced level in the plasma membrane and higher degradation rate through the proteasomal or lysosomal routes These (e.g., the frequent V12M polymorphism or the naturally occurring D620N and K360del variants) result in the expression of fully functional ABCG2, with unchanged (or even somewhat increased) plasma membrane appearance, stability, and activity. These variants, including the Q141K polymorphism and the rare M71V mutation, are good candidates for trafficking correction by small molecules. The experimental validation of these potential interactions is still needed

Conclusions

Findings

In Silico Methodologies