Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

Judith Peters; Andrea Rittger; Rebecca Weisner; Johannes Knabbe; Friederike Zunke; Michelle Rothaug; Markus Damme; Samuel F. Berkovic; Judith Blanz; Paul Saftig; Michael Schwake

doi:10.1016/j.bbrc.2014.12.111

Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

Judith Peters, Andrea Rittger, Rebecca Weisner, Johannes Knabbe, Friederike Zunke, Michelle Rothaug, Markus Damme, Samuel F. Berkovic, Judith Blanz, Paul Saftig, Michael Schwake^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	334-340
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	457
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2014.12.111
State	Published - Feb 13 2015

Keywords

Cathepsin-F
Kufs disease
LIMP-2
Lysosomal storage disease
Neuronal ceroid-lipofuscinosis

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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Peters, J., Rittger, A., Weisner, R., Knabbe, J., Zunke, F., Rothaug, M., Damme, M., Berkovic, S. F., Blanz, J., Saftig, P., & Schwake, M. (2015). Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease. Biochemical and Biophysical Research Communications, 457(3), 334-340. https://doi.org/10.1016/j.bbrc.2014.12.111

@article{b5c317c3df9046a2b0d72130a1b7dc75,

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.",

keywords = "Cathepsin-F, Kufs disease, LIMP-2, Lysosomal storage disease, Neuronal ceroid-lipofuscinosis",

author = "Judith Peters and Andrea Rittger and Rebecca Weisner and Johannes Knabbe and Friederike Zunke and Michelle Rothaug and Markus Damme and Berkovic, {Samuel F.} and Judith Blanz and Paul Saftig and Michael Schwake",

note = "Funding Information: We thank Lisa Andresen and Maike Langer for excellent technical support. This work was supported by the Research Training Group ( GRK 1459 ) of the Deutsche Forschungsgemeinschaft (DFG) to JB and MS and a Boehringer Ingelheim grant to FZ. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc. All rights reserved.",

year = "2015",

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day = "13",

doi = "10.1016/j.bbrc.2014.12.111",

language = "English (US)",

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Peters, J, Rittger, A, Weisner, R, Knabbe, J, Zunke, F, Rothaug, M, Damme, M, Berkovic, SF, Blanz, J, Saftig, P & Schwake, M 2015, 'Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease', Biochemical and Biophysical Research Communications, vol. 457, no. 3, pp. 334-340. https://doi.org/10.1016/j.bbrc.2014.12.111

TY - JOUR

T1 - Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

AU - Peters, Judith

AU - Rittger, Andrea

AU - Weisner, Rebecca

AU - Knabbe, Johannes

AU - Zunke, Friederike

AU - Rothaug, Michelle

AU - Damme, Markus

AU - Berkovic, Samuel F.

AU - Blanz, Judith

AU - Saftig, Paul

AU - Schwake, Michael

N1 - Funding Information: We thank Lisa Andresen and Maike Langer for excellent technical support. This work was supported by the Research Training Group ( GRK 1459 ) of the Deutsche Forschungsgemeinschaft (DFG) to JB and MS and a Boehringer Ingelheim grant to FZ. Publisher Copyright: © 2015 Elsevier Inc. All rights reserved.

PY - 2015/2/13

Y1 - 2015/2/13

N2 - 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.

AB - 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.

KW - Cathepsin-F

KW - Kufs disease

KW - LIMP-2

KW - Lysosomal storage disease

KW - Neuronal ceroid-lipofuscinosis

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SN - 0006-291X

VL - 457

SP - 334

EP - 340

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

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ER -

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

Keywords

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