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

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


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.

MeSH terms

  • Aspartic Acid Endopeptidases / metabolism*
  • Cell Line
  • Endosomes / metabolism*
  • Humans
  • Lysosome-Associated Membrane Glycoproteins
  • Lysosomes / metabolism
  • Membrane Proteins / metabolism*
  • Neuronal Ceroid-Lipofuscinoses / metabolism*
  • Protein Transport
  • Solubility
  • trans-Golgi Network / metabolism


  • CLN5 protein, human
  • Lysosome-Associated Membrane Glycoproteins
  • Membrane Proteins
  • Aspartic Acid Endopeptidases