Histones deacetylase inhibitors mediate rescue of the ABCG2 Q141K variant: potential for a new treatment for gout

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NCI	MOLBIO-1

* FARE Award Winner

Authors

• A Basseville
• A Tamaki
• C Ierano
• Y Ward
• RW Robey
• RS Hegde
• SE Bates

Abstract

ABCG2 is an ATP-binding cassette transporter, initially known by its involvement in drug efflux. Recently, the Q141K polymorphism in ABCG2 gene was associated with elevated serum urate levels and gout. The polymorphism impairs the normal expression, localization and function of ABCG2. We have studied the biology underlying altered expression and localization of ABCG2 Q141K, and screened compounds for their ability to restore proper function and localization of the variant. ABCG2 Q141K variant was fully processed but mainly retained in the aggresome, a perinuclear structure. Colchicine, a microtubule disruptor, induced relocalization of the variant from the aggresome to the cell surface. Histone deacetylase inhibitors (HDIs) induced not only relocalization to cell surface, but also restored protein expression to levels similar to the wild-type, coupled with increased ABCG2 specific efflux. HDIs did not modify the aggresome structure, rescued only neosynthesized proteins, and were redundant with colchicine in relocalization. We postulate that colchicine-induced Q141K ABCG2 relocalization involves inhibition of retrograde transport of the variant to the aggresome. In another way, HDI-induced ABCG2 Q141K rescue occurred at multiple levels by modulating the protein transcription, folding and trafficking. These results open doors for a new use of HDIs in the treatment of gout.

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