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J. Biol. Chem., Vol. 280, Issue 11, 10277-10283, March 18, 2005

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AP-1 and AP-3 Facilitate Lysosomal Targeting of Batten Disease Protein CLN3 via Its Dileucine Motif^*

Aija Kyttälä¶, Kristiina Yliannala, Peter Schu||, Anu Jalanko, and J. Paul Luzio

From the National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, FIN-00290 Helsinki, Finland, Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Hills Road, Cambridge CB2 2XY, United Kingdom, and ^||University of Göttingen, Center for Biochemistry and Molecular Cell Biology, Biochemistry II, 37073 Göttingen, Germany

CLN3 is a transmembrane protein with a predominant localization in lysosomes in non-neuronal cells but is also found in endosomes and the synaptic region in neuronal cells. Mutations in the CLN3 gene result in juvenile neuronal ceroid lipofuscinosis or Batten disease, which currently is the most common cause of childhood dementia. We have recently reported that the lysosomal targeting of CLN3 is facilitated by two targeting motifs: a dileucine-type motif in a cytoplasmic loop domain and an unusual motif in the carboxyl-terminal cytoplasmic tail comprising a methionine and a glycine separated by nine amino acids (Kyttälä, A., Ihrke, G., Vesa, J., Schell, M. J., and Luzio, J. P. (2004) Mol. Biol. Cell 15, 1313–1323). In the present study, we investigated the pathways and mechanisms of CLN3 sorting using biochemical binding assays and immunofluorescence methods. The dileucine motif of CLN3 bound both AP-1 and AP-3 in vitro, and expression of mutated CLN3 in AP-1- or AP-3-deficient mouse fibroblasts showed that both adaptor complexes are required for sequential sorting of CLN3 via this motif. Our data indicate the involvement of complex sorting machinery in the trafficking of CLN3 and emphasize the diversity of parallel and sequential sorting pathways in the trafficking of membrane proteins.

Received for publication, October 19, 2004 , and in revised form, December 10, 2004.

^* This work was supported by Traveling Research Fellowships Grant 061077 (to A. K.) and Grant 057263 (to J. P. L.) from the Wellcome Trust (UK), by a Medical Research Council (UK) grant (to J. P. L.), and by Centre of Excellence Grant 44870 from the Academy of Finland and European Community Grant LSHM-CT-2003-503051 (to A. K., K. Y., and A. J.). The Cambridge Institute for Medical Research is in receipt of a strategic award from the Wellcome Trust. 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.

^¶ To whom correspondence should be addressed: Aija Kyttälä, National Public Health Institute, Dept. of Molecular Medicine, Biomedicum Helsinki, P. O. B. 104, FIN-00251 Helsinki, Finland. Tel.: 3589-47448554; Fax: 3589-47448480; E-mail: aija.kyttala{at}ktl.fi.

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