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Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation
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Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation
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Journal Article
Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation
2023
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/1
/ 13/106
/ 13/31
/ 14/19
/ 14/28
/ 14/34
/ 14/35
/ 14/63
/ 42/89
/ Enzymes
/ Humanities and Social Sciences
/ Humans
/ Mannose
/ Membrane Glycoproteins - genetics
/ Membrane Glycoproteins - metabolism
/ Molecular Chaperones - metabolism
/ Mutation
/ Neuronal ceroid lipofuscinosis
/ Neuronal Ceroid-Lipofuscinoses - genetics
/ Neuronal Ceroid-Lipofuscinoses - metabolism
/ Proteins
/ Receptor, IGF Type 2 - genetics
/ Receptor, IGF Type 2 - metabolism
/ Science
/ Tubules
