title: Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments.
abstract: CLN3 is an endosomal/lysosomal transmembrane protein mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder. The function of CLN3 in endosomal/lysosomal events has remained elusive due to poor understanding of its interactions in these compartments. It has previously been shown that the localisation of late endosomal/lysosomal compartments is disturbed in cells expressing the most common disease-associated CLN3 mutant, CLN3∆ex7-8 (c.462-677del). We report here that a protracted disease causing mutant, CLN3E295K, affects the properties of late endocytic compartments, since over-expression of the CLN3E295K mutant protein in HeLa cells induced relocalisation of Rab7 and a perinuclear clustering of late endosomes/lysosomes. In addition to the previously reported disturbances in the endocytic pathway, we now show that the anterograde transport of late endosomal/lysosomal compartments is affected in CLN3 deficiency. CLN3 interacted with motor components driving both plus and minus end microtubular trafficking: tubulin, dynactin, dynein and kinesin-2. Most importantly, CLN3 was found to interact directly with active, guanosine-5'-triphosphate (GTP)-bound Rab7 and with the Rab7-interacting lysosomal protein (RILP) that anchors the dynein motor. The data presented in this study provide novel insights into the role of CLN3 in late endosomal/lysosomal membrane transport.
authors.affiliation: National Institute for Health and Welfare and FIMM, Institute for Molecular Medicine Finland, Biomedicum Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Uusi-Rauva
authors.forename: Aija
authors.initials: A
authors.lastname: Kyttälä
authors.forename: Rik
authors.initials: R
authors.lastname: van der Kant
authors.forename: Jouni
authors.initials: J
authors.lastname: Vesa
authors.forename: Kimmo
authors.initials: K
authors.lastname: Tanhuanpää
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
mesh_terms: D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D020409:Molecular Motor Proteins / Q000378:metabolism*; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D020409:Molecular Motor Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D020691:rab GTP-Binding Proteins