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J. Biol. Chem., Vol. 281, Issue 11, 7294-7301, March 17, 2006

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TRP-ML1 Regulates Lysosomal pH and Acidic Lysosomal Lipid Hydrolytic Activity^*

Abigail A. Soyombo, Sandra Tjon-Kon-Sang, Youssef Rbaibi, Enkelejda Bashllari, Jill Bisceglia, Shmuel Muallem¹, and Kirill Kiselyov

From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Mucolipidosis type IV (MLIV) is caused by mutations in the ion channel mucolipin 1 (TRP-ML1). MLIV is typified by accumulation of lipids and membranous materials in intracellular organelles, which was hypothesized to be caused by the altered membrane fusion and fission events. How mutations in TRP-ML1 lead to aberrant lipolysis is not known. Here we present evidence that MLIV is a metabolic disorder that is not associated with aberrant membrane fusion/fission events. Thus, measurement of lysosomal pH revealed that the lysosomes in TRP-ML1^-/- cells obtained from the patients with MLIV are over-acidified. TRP-ML1 can function as a H⁺ channel, and the increased lysosomal acidification in TRP-ML1^-/- cells is likely caused by the loss of TRP-ML1-mediated H⁺ leak. Measurement of lipase activity using several substrates revealed a marked reduction in lipid hydrolysis in TRP-ML1^-/- cells, which was rescued by the expression of TRP-ML1. Cell fractionation indicated specific loss of acidic lipase activity in TRP-ML1^-/- cells. Furthermore, dissipation of the acidic lysosomal pH of TRP-ML1^-/- cells by nigericin or chloroquine reversed the lysosomal storage disease phenotype. These findings provide a new mechanism to account for the pathogenesis of MLIV.

Received for publication, July 27, 2005 , and in revised form, December 14, 2005.

^* This work was supported in part by National Institutes of Health Grants DE12309 and DK38938 (to S. M), a Mucolipidosis Foundation grant (to A. A. S.), and the Pittsburgh Life Science Greenhouse startup fund (to K. K.). 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: Dept. of Physiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9040. Tel.: 214-645-6008; E-mail: shmuel.muallem{at}utsouthwestern.edu.

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