Calcagni', Alessia, Staiano, Leopoldo, Zampelli, Nicolina, Minopoli, Nadia, Herz, Niculin J., Di Tullio, Giuseppe, Huynh, Tuong, Monfregola, Jlenia, Esposito, Alessandra, Cirillo, Carmine, Bajic, Aleksandar, Zahabiyon, Mahla, Curnock, Rachel, Polishchuk, Elena, Parkitny, Luke, Medina, Diego Luis, Pastore, Nunzia, Cullen, Peter J., Parenti, Giancarlo, and De Matteis, Maria Antonietta
Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease. CLN3 mutations cause Batten disease, a devastating neurodegenerative lysosomal storage disease. Here, the authors discovered that CLN3 plays a crucial role in both trafficking of lysosomal proteins and autophagic lysosomal reformation. [ABSTRACT FROM AUTHOR]