TY  - JOUR
AU  - Jules, Felix
AU  - Sauvageau, Etienne
AU  - Dumaresq-Doiron, Karine
AU  - Mazzaferri, Javier
AU  - Haug-Kröper, Martina
AU  - Fluhrer, Regina
AU  - Costantino, Santiago
AU  - Lefrancois, Stephane
TI  - CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein.
JO  - Experimental cell research
VL  - 357
IS  - 1
SN  - 0014-4827
CY  - Orlando, Fla.
PB  - Academic Press
M1  - DZNE-2020-05660
SP  - 40-50
PY  - 2017
AB  - 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.
KW  - Lysosome-Associated Membrane Glycoproteins
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Cell Line
KW  - Endosomes: metabolism
KW  - Humans
KW  - Lysosomes: metabolism
KW  - Membrane Proteins: metabolism
KW  - Neuronal Ceroid-Lipofuscinoses: metabolism
KW  - Protein Transport
KW  - Solubility
KW  - trans-Golgi Network: metabolism
KW  - CLN5 protein, human (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28442266
DO  - DOI:10.1016/j.yexcr.2017.04.024
UR  - https://pub.dzne.de/record/139338
ER  -