title: Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease.
abstract: The lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) has been identified as a receptor for enterovirus 71 uptake and mannose-6-phosphate-independent lysosomal trafficking of the acid hydrolase β-glucocerebrosidase. Here we show that LIMP-2 undergoes proteolytic cleavage mediated by lysosomal cysteine proteases. Heterologous expression and in vitro studies suggest that cathepsin-F is mainly responsible for the lysosomal processing of wild-type LIMP-2. Furthermore, examination of purified lysosomes revealed that LIMP-2 undergoes proteolysis in vivo. Mutations in the gene encoding cathepsin-F (CTSF) have recently been associated with type-B-Kufs-disease, an adult form of neuronal ceroid-lipofuscinosis. In this study we show that disease-causing cathepsin-F mutants fail to cleave LIMP-2. Our findings provide evidence that LIMP-2 represents an in vivo substrate of cathepsin-F with relevance for understanding the pathophysiology of type-B-Kufs-disease.
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Peters
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rittger
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Weisner
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Knabbe
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Zunke
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rothaug
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Damme
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Blanz
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Biochemie III, Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, D-33615, Germany. Electronic address: michael.schwake@uni-bielefeld.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056646:Cathepsin F / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D059748:Proteolysis; D051116:Receptors, Scavenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D018955:CD36 Antigens; D051907:Lysosomal Membrane Proteins; D050505:Mutant Proteins; D051116:Receptors, Scavenger; D011994:Recombinant Proteins; C074299:SCARB2 protein, human; C489452:Scarb2 protein, mouse; C534090:CTSF protein, human; D056646:Cathepsin F; C534092:Ctsf protein, mouse
keywords: Cathepsin-F; Kufs disease; LIMP-2; Lysosomal storage disease; Neuronal ceroid-lipofuscinosis