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Exp Cell Res. 2017 Aug 1;357(1):40-50. doi: 10.1016/j.yexcr.2017.04.024. Epub 2017 Apr 22.

CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein.

Author information

1
Centre INRS-Institut Armand-Frappier, INRS, Laval, Canada H7V 1B7.
2
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Canada H1T 2M4.
3
Biomedical Center (BMC), Institute for Metabolic Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
4
Biomedical Center (BMC), Institute for Metabolic Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
5
Département d'Ophtalmologie et Institut de Génie Biomédical, Université de Montréal, Montréal, Canada H3T 1J4; Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Canada H1T 2M4.
6
Centre INRS-Institut Armand-Frappier, INRS, Laval, Canada H7V 1B7; Department of Anatomy and Cell Biology, McGill University, Montreal, Canada H3A 2B2. Electronic address: stephane.lefrancois@iaf.inrs.ca.

Abstract

The Neuronal ceroid lipofuscinoses (NCLs) are a group of recessive disorders of childhood with overlapping symptoms including vision loss, ataxia, cognitive regression and premature death. 14 different genes have been linked to NCLs (CLN1-CLN14), but the functions of the proteins encoded by the majority of these genes have not been fully elucidated. Mutations in the CLN5 gene are responsible for the Finnish variant late-infantile form of NCL (Finnish vLINCL). CLN5 is translated as a 407 amino acid transmembrane domain containing protein that is heavily glycosylated, and subsequently cleaved into a mature soluble protein. Functionally, CLN5 is implicated in the recruitment of the retromer complex to endosomes, which is required to sort the lysosomal sorting receptors from endosomes to the trans-Golgi network. The mechanism that processes CLN5 into a mature soluble protein is currently not known. Herein, we demonstrate that CLN5 is initially translated as a type II transmembrane protein and subsequently cleaved by SPPL3, a member of the SPP/SPPL intramembrane protease family, into a mature soluble protein consisting of residues 93-407. The remaining N-terminal fragment is then cleaved by SPPL3 and SPPL2b and degraded in the proteasome. This work further characterizes the biology of CLN5 in the hopes of identifying a novel therapeutic strategy for affected children.

KEYWORDS:

CLN5; Endosomes; Intracellular trafficking; Neurodegeneration; Neuronal ceroid lipofuscinosis; Signal Peptide Peptidase-like proteases

PMID:
28442266
DOI:
10.1016/j.yexcr.2017.04.024
[Indexed for MEDLINE]

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