Sumoylation: A Novel Mechanism for Regulating Drug/Xenobiotic Transporters OATs

Project Summary Organic anion transporters (OATs) mediate the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-cancer drugs, anti-viral agents, diuretics, antibiotics, anti-hypertensives, and anti-inflammatories. OATs are abundantly expressed in kidney, liver, brain, and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological, and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug disposition through OAT pathway. During the previous grant period, significant progress and productivity have been achieved, and the new findings from this period led to the establishment of a fine-tuned research plan and strategy in this competing renewal. We propose to test the novel hypothesis that post-translational modification of OAT by SUMO conjugation is an important means of controlling the stability, subcellular localization, and activity of the transporter. Three Specific Aims are outlined. In Specific Aim I, we will identify the nature of OAT sumoylation. In Specific Aim II, we will assess the role of sumoylation in OAT-mediated drug transport in cultured cells. In Specific Aim III, we will evaluate the physiological and pathophysiological relevance of sumoylation in OAT-mediated drug transport. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in cultured cells, in tissue slices, and in animals. Understanding the role of sumoylation in the regulation of OATs, a novel focus in drug transport field, will have significant impact on the future design of strategies aimed at maximizing therapeutic efficacy and minimizing toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.