Organelle biogenesis requires proper transport of proteins from their site of synthesis to their target subcellular compartment1,2,3. Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and traffic through the Golgi complex before being transferred to the endolysosomal system4,5,6, but how they are transferred from the ER to the Golgi is unknown. Here, we show that ER-to-Golgi transfer of lysosomal enzymes requires CLN8, an ER-associated membrane protein whose loss of function leads to the lysosomal storage disorder, neuronal ceroid lipofuscinosis 8 (a type of Batten disease)7. ER-to-Golgi trafficking of CLN8 requires interaction with the COPII and COPI machineries via specific export and retrieval signals localized in the cytosolic carboxy terminus of CLN8. CLN8 deficiency leads to depletion of soluble enzymes in the lysosome, thus impairing lysosome biogenesis. Binding to lysosomal enzymes requires the second luminal loop of CLN8 and is abolished by some disease-causing mutations within this region. Our data establish an unanticipated example of an ER receptor serving the biogenesis of an organelle and indicate that impaired transport of lysosomal enzymes underlies Batten disease caused by mutations in CLN8.
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The authors declare that the main data supporting the findings of this study are available within the article and its Supplementary Information files. Source data for Figs. 1–5 and Supplementary Figs. 2–5 have been provided as Supplementary Table 1. All other data supporting the findings of this study are available from the corresponding author upon request. Mass spectrometry data have been deposited in ProteomeXchange with the primary accession code PXD011066. The GEO accession numbers of the microarray data sets analysed for the co-expression analysis are the following: GDS1237, GDS1249, GDS1344, GDS1369, GDS1411, GDS1413, GDS1427, GDS1439, GDS1553, GDS1579, GDS1580, GDS1604, GDS1617, GDS1665, GDS1667, GDS1673, GDS1685, GDS1732, GDS1779, GDS1807, GDS1812, GDS1869, GDS1917, GDS1962, GDS1973, GDS1989, GDS2010, GDS2023, GDS2046, GDS2052, GDS2083, GDS2088, GDS2089, GDS2118, GDS2125, GDS2154, GDS2164, GDS2189, GDS2204, GDS2213, GDS2215, GDS2216, GDS2221, GDS2250, GDS2251, GDS2307, GDS2339, GDS2374, GDS2414, GDS2416, GDS2418, GDS2426, GDS2431, GDS2432, GDS2453, GDS2470, GDS2471, GDS2484, GDS2486, GDS2491, GDS2495, GDS2499, GDS2526, GDS2534, GDS2548, GDS2565, GDS2604, GDS2609, GDS2611, GDS2615, GDS2628, GDS2635, GDS2653, GDS2657, GDS2697, GDS2724, GDS2728, GDS2737, GDS2749, GDS2750, GDS2755, GDS2760, GDS2772, GDS2779, GDS2782, GDS2789, GDS2794, GDS2819, GDS2821, GDS2822, GDS2832, GDS2835, GDS2838, GDS2860, GDS2902, GDS2919, GDS2935, GDS2958, GDS2959, GDS3062, GDS3217, GDS3220, GDS3223 and GDS651.
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We thank P. Lobel, D. Pearce, J. Cooper, T. Dierks, M. Damme, Z. Liu and S. Elsea for helpful discussion; A. Schiano and M. Rousseaux for technical assistance; H. Zoghbi, V. Brandt, A. Ballabio, H. Jafar-Nejad, K. Venkatachalam and M. Wang for critical reading of the manuscript; and B. Turk (J. Stefan Institute, Slovenia), K. Yamada (Institute for Developmental Research, Japan), B. Blazar (University of Minnesota, USA), D. Kohn (University of California, Los Angeles, USA), T. Beccari (Università degli Studi di Perugia, Italy) and M. Peterfy (University of California, Los Angeles, USA) for providing plasmids encoding lysosomal proteins or other tested proteins. This work was supported by the NIH grant NS079618 (to M.S.) and grants from the Beyond Batten Disease Foundation (to M.S.) and the NCL-Stiftung (to M.S.). This project was supported in part by the Hamill Foundation and by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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Nature Cell Biology (2018)