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Abstract Number: 2274

Evidence of Phospho-Degron Regulating Expression of Urate Secretory Transporter ABCG2

Alexis Hofherr1, Meng Li2, Michael Kottgen1 and Owen M. Woodward2, 1Nephrology, University of Freiburg Medical Center, Freiburg, Germany, 2Physiology, University of Maryland School of Medicine, Baltimore, MD

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Gout and uric acid

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Session Information

Date: Tuesday, November 15, 2016

Session Title: Metabolic and Crystal Arthropathies - Poster II: Epidemiology and Mechanisms of Disease

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:  ABCG2 is a high capacity urate secretory transporter of the renal proximal tubule. The common Q141K ABCG2 mutation causes gout in humans through an increased instability of the nucleotide-binding domain leading to enhanced degradation and reduced function.

Methods: Typical biochemical and cell biological techniques

Results:  Here, we found ABCG2 protein rescued from degradation with the proteasome inhibitor MG-132 is phosphorylated; raising the possibility that a phospho-degron regulates ABCG2 trafficking and expression. An in silicoanalysis of ABCG2 revealed a limited number of predicted phosphorylation sites, including S195, a serine conserved in the mammalian lineage. The upstream RXRXS represents a target motif for AKT1 and PKA, which both co-immunoprecipitated with ABCG2. Specifically, endogenous AKT1 pulled down both over expressed ABCG2 in HEK293 cells as well as endogenous ABCG2 in mouse kidney lysate. AKT1 and ABCG2 transcript co-localize in the proximal S2 segment of the mammalian nephron and inhibiting the AKT1 kinase cascade with PI3K inhibitor LY294002, or with growth factor receptor (RTK) inhibitor Vandetanib, dramatically up-regulated ABCG2 expression. Conversely, activating the AKT1 cascade with FBS down-regulated ABCG2 expression. Replacement of the S195 residue with a phosphomimetic aspartic acid resulted in significant reduction in ABCG2 expression, localization of ABCG2 to peri-nuclear compartments, and significant sensitivity to MG-132; confirming the S195 residue as a phospho-degron. Finally, a non-phosphorylatable S195A substitution led to the complete rescue of the Q141K gout mutant protein expression and trafficking.

Conclusion: Modeled ABCG2 structure indicates phosphorylation of the S195 residue may only be possible when the nucleotide-binding domains are separated, suggesting the S195 phospho-degron may be part of a novel regulatory mechanism for function and trafficking in ABC transporters. Funded by: American Heart Association 14SDG18060004 & Ardea BioSciences.


Disclosure: A. Hofherr, None; M. Li, None; M. Kottgen, None; O. M. Woodward, Ardea BioSciences, 2,AstraZeneca, 1.

To cite this abstract in AMA style:

Hofherr A, Li M, Kottgen M, Woodward OM. Evidence of Phospho-Degron Regulating Expression of Urate Secretory Transporter ABCG2 [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/evidence-of-phospho-degron-regulating-expression-of-urate-secretory-transporter-abcg2/. Accessed January 20, 2021.
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