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J. Biol. Chem., Vol. 281, Issue 15, 10273-10280, April 14, 2006

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Saccharomyces cerevisiae Lacking Btn1p Modulate Vacuolar ATPase Activity to Regulate pH Imbalance in the Vacuole^*

Sergio Padilla-López and David A. Pearce^¶1

From the Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, the Department of Biochemistry and Biophysics, and the ^¶Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

The vacuolar H⁺-ATPase (V-ATPase) along with ion channels and transporters maintains vacuolar pH. V-ATPase ATP hydrolysis is coupled with proton transport and establishes an electrochemical gradient between the cytosol and vacuolar lumen for coupled transport of metabolites. Btn1p, the yeast homolog to human CLN3 that is defective in Batten disease, localizes to the vacuole. We previously reported that Btn1p is required for vacuolar pH maintenance and ATP-dependent vacuolar arginine transport. We report that extracellular pH alters both V-ATPase activity and proton transport into the vacuole of wild-type Saccharomyces cerevisiae. V-ATPase activity is modulated through the assembly and disassembly of the V₀ and V₁ V-ATPase subunits located in the vacuolar membrane and on the cytosolic side of the vacuolar membrane, respectively. V-ATPase assembly is increased in yeast cells grown in high extracellular pH. In addition, at elevated extracellular pH, S. cerevisiae lacking BTN1 (btn1-), have decreased V-ATPase activity while proton transport into the vacuole remains similar to that for wild type. Thus, coupling of V-ATPase activity and proton transport in btn1- is altered. We show that down-regulation of V-ATPase activity compensates the vacuolar pH imbalance for btn1- at early growth phases. We therefore propose that Btn1p is required for tight regulation of vacuolar pH to maintain the vacuolar luminal content and optimal activity of this organelle and that disruption in Btn1p function leads to a modulation of V-ATPase activity to maintain cellular pH homeostasis and vacuolar luminal content.

Received for publication, September 28, 2005 , and in revised form, January 11, 2006.

^* This work was supported by National Institutes of Health Grant R01-NS036610. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Center for Aging and Developmental Biology, Box 645, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. Tel.: 585-273-1514; Fax: 585-276-1972; E-mail: David_Pearce{at}urmc.rochester.edu.

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