期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1865, 期 10, 页码 1437-1450出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2018.07.017
关键词
Batten disease; CLN5; Dictyostelium discoideum; Neuronal ceroid lipofuscinoses; Secretion
资金
- Trent University
- Canada Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
Mutations in CLN5 cause neuronal ceroid lipofuscinosis (NCL), a currently untreatable neurodegenerative disorder commonly known as Batten disease. Several genetic models have been generated to study the function of CLN5, but one limitation has been the lack of a homolog in lower eukaryotic model systems. Our previous work revealed a homolog of CLN5 in the social amoeba Dictyostelium discoideum. We used a Cln5-GFP fusion protein to show that the protein is secreted and functions as a glycoside hydrolase in Dictyostelium. Importantly, we also revealed this to be the molecular function of human CLN5. In this study, we generated an antibody against Cln5 to show that the endogenous protein is secreted during the early stages of Dictyostelium development. Like human CLN5, the Dictyostelium homolog is glycosylated and requires this post-translational modification for secretion. Cln5 secretion bypasses the Golgi complex, and instead, occurs via an unconventional pathway linked to autophagy. Interestingly, we observed co-localization of Cln5 and GFP-Cln3 as well as increased secretion of Cln5 and Cln5-GFP in cin3(-) cells. Loss of Cln5 causes defects in adhesion and chemotaxis, which intriguingly, has also been reported for Dictyostelium cells lacking Cln3. Finally, autofluorescence was detected in cln5(-) cells, which is consistent with observations in mammalian systems. Together, our data support a function for Cln5 during the early stages of multicellular development, provide further evidence for the molecular networking of NCL proteins, and provide insight into the mechanisms that may underlie CLN5 function in humans.
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