CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis

Alberto di Ronza, Lakshya Bajaj, Jaiprakash Sharma, Deepthi Sanagasetti, Parisa Lotfi, Carolyn Joy Adamski, John Collette, Michela Palmieri, Abdallah Amawi, Lauren Popp, Kevin Tommy Chang, Maria Chiara Meschini, Hon Chiu Eastwood Leung, Laura Segatori, Alessandro Simonati, Richard Norman Sifers, Filippo Maria Santorelli, Marco Sardiello

Research output: Contribution to journalLetterpeer-review

70 Scopus citations


Organelle biogenesis requires proper transport of proteins from their site of synthesis to their target subcellular compartment 1–3 . Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and traffic through the Golgi complex before being transferred to the endolysosomal system 4–6 , 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.

Original languageEnglish
Pages (from-to)1370-1377
Number of pages8
JournalNature Cell Biology
Issue number12
StatePublished - Dec 1 2018


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