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Vol. 15, Issue 3, 1313-1323, March 2004

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Two Motifs Target Batten Disease Protein CLN3 to Lysosomes in Transfected Nonneuronal and Neuronal Cells

Aija Kyttälä ^*, Gudrun Ihrke ^*, Jouni Vesa , Michael J. Schell , and J. Paul Luzio ^* 

^* Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Cambridge CB2 2XY, United Kingdom; David Geffen School of Medicine at University of California, Los Angeles, California 90095-7088; and Department of Pharmacology, University of Cambridge, Cambridge CB2 1QJ, United Kingdom

Submitted February 28, 2003; Revised October 20, 2003; Accepted October 23, 2003
Monitoring Editor: Guido Guidotti

Batten disease is a neurodegenerative disorder resulting from mutations in CLN3, a polytopic membrane protein, whose predominant intracellular destination in nonneuronal cells is the lysosome. The topology of CLN3 protein, its lysosomal targeting mechanism, and the development of Batten disease are poorly understood. We provide experimental evidence that both the N and C termini and one large loop domain of CLN3 face the cytoplasm. We have identified two lysosomal targeting motifs that mediate the sorting of CLN3 in transfected nonneuronal and neuronal cells: an unconventional motif in the long C-terminal cytosolic tail consisting of a methionine and a glycine separated by nine amino acids [M(X)₉G], and a more conventional dileucine motif, located in the large cytosolic loop domain and preceded by an acidic patch. Each motif on its own was sufficient to mediate lysosomal targeting, but optimal efficiency required both. Interestingly, in primary neurons, CLN3 was prominently seen both in lysosomes in the cell body and in endosomes, containing early endosomal antigen-1 along neuronal processes. Because there are few lysosomes in axons and peripheral parts of dendrites, the presence of CLN3 in endosomes of neurons may be functionally important. Endosomal association of the protein was independent of the two lysosomal targeting motifs.

Abbreviations used: CI-M6PR, cation-independent mannose 6-phosphate receptor; EEA1, early endosomal antigen-1; GST, glutathione S-transferase; lgp, lysosomal membrane glycoprotein; NCL, neuronal ceroid lipofuscinosis; NRK, normal rat kidney; PDI, protein disulfide isomerase; PBS, phosphate-buffered saline; PFA, paraformaldehyde; TMD, transmembrane domain; wt, wild type.

Corresponding author. E-mail address: jpl10{at}cam.ac.uk.

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