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

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.

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

“…1). The interaction between CLN3 and CLN5 could be due to their common link to Rab7 and the retromer complex, while the binding of CLN5 to CLN6 and CLN8 could indicate that these proteins play a role in processing CLN5 to its mature form in the ER [84][85][86]. Finally, CTSD/CLN10 has been shown to interact with PGRN/CLN11 in HEK293T cells, which could possibly be explained by the observations that both proteins are secreted [29,38,79,80] (Table 2, Fig.…”

Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease

“…43 Unfortunately, a number of workers have assumed that the first ATG in the human CLN5 gene is the start codon, leading to deductions from function and localization studies of uncertain veracity. 44,45 This must be borne in mind when designing vectors expressing the CLN5 protein for human treatments.…”

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

“…Consistent with its localization to the lysosomal lumen, CLN5 is heavily glycosylated [61,62]. CLN5 is translated as a single transmembrane domain containing protein [59,63], but then undergoes Nterminal cleavage in the ER by a member of the signal peptide peptidase (SPP) and SSP-like (SSPL) family, after which it is then further transported as a soluble protein [61,64,65]. However, the mechanism by which CLN5 is transported to the lysosome is not yet fully defined.…”