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J. Biol. Chem., Vol. 281, Issue 25, 17517-17527, June 23, 2006

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Lysosomal Localization of TRPML3 Depends on TRPML2 and the Mucolipidosis-associated Protein TRPML1^*

Kartik Venkatachalam, Thomas Hofmann, and Craig Montell¹

From the Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and the Institut fuer Pharmakologie und Toxikologie, Philipps-Universitaet Marburg, Karl-von-Frisch-Strasse 1, 35033 Marburg, Germany

Mucolipidosis type IV is an autosomal recessive lysosomal storage disorder characterized by severe neurodegeneration, achlorhydria, and visual impairments such as corneal opacity and strabismus. The disease arises due to mutations in a group 2 transient receptor potential (TRP)-related cation channel, TRPML1. Mammals encode two additional TRPML proteins named TRPML2 and TRPML3. Information regarding the propensity of these proteins to multimerize, their subcellular distribution and mechanisms that regulate their trafficking are limited. Here we demonstrate that TRPMLs interact to form homo- and heteromultimers. Moreover, the presence of either TRPML1 or TRPML2 specifically influences the spatial distribution of TRPML3. TRPML1 and TRPML2 homomultimers are lysosomal proteins, whereas TRPML3 homomultimers are in the endoplasmic reticulum. However, TRPML3 localizes to lysosomes when coexpressed with either TRPML1 or TRPML2 and is comparably mislocalized when lysosomal targeting of TRPML1 and TRPML2 is disrupted. Conversely, TRPML3 does not cause retention of TRPML1 or TRPML2 in the endoplasmic reticulum. These data demonstrate that there is a hierarchy controlling the subcellular distributions of the TRPMLs such that TRPML1 and TRPML2 dictate the localization of TRPML3 and not vice versa.

Received for publication, January 26, 2006 , and in revised form, April 7, 2006.

^* This work was supported by NEI/National Institutes of Health Grant EY10852 (to C. M.) and by the Mucolipidosis Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5.

¹ To whom correspondence should be addressed: Dept. of Biological Chemistry and Dept. of Neuroscience, The Johns Hopkins University School of Medicine, 408 Wood Basic Sciences Bldg., 725 N. Wolfe St., Baltimore, MD 21205. Tel.: 410-955-1199; Fax: 410-614-9573; E-mail: cmontell{at}jhmi.edu.

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