Physiological shedding and C-terminal proteolytic processing of TMEM106B
Sebastian Held,
Christian Erck,
Susanna Kemppainen,
Florian Bleibaum,
Neha Jadhav Giridhar,
Regina Feederle,
Claudia Krenner,
Sini-Pauliina Juopperi,
Anna Calliari,
Torben Mentrup,
Bernd Schröder,
Dennis W. Dickson,
Tuomas Rauramaa,
Leonard Petrucelli,
Mercedes Prudencio,
Mikko Hiltunen,
Patrick Lüningschrör,
Anja Capell,
Markus Damme
Affiliations
Sebastian Held
Institute of Biochemistry, Christian-Albrechts-University Kiel, Olshausenstrasse 40, 24118 Kiel, Germany
Christian Erck
Cellular Proteome Research, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Synaptic Systems GmbH, Rudolf-Wissell-Straβe 28a, 37079 Göttingen, Germany
Susanna Kemppainen
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Florian Bleibaum
Institute of Biochemistry, Christian-Albrechts-University Kiel, Olshausenstrasse 40, 24118 Kiel, Germany
Neha Jadhav Giridhar
Institute of Clinical Neurobiology, University Hospital Würzburg, Versbacher Str. 5, 97078 Würzburg, Germany
Regina Feederle
Monoclonal Antibody Core Facility, German Research Center for Environmental Health, Neuherberg, Germany; Munich Center for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
Claudia Krenner
Division of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
Sini-Pauliina Juopperi
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Anna Calliari
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Torben Mentrup
Institute of Physiological Chemistry, Medizinische Fakultät und Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Bernd Schröder
Institute of Physiological Chemistry, Medizinische Fakultät und Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Dennis W. Dickson
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Tuomas Rauramaa
Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland; Unit of Pathology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
Leonard Petrucelli
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Mercedes Prudencio
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Mikko Hiltunen
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Patrick Lüningschrör
Institute of Clinical Neurobiology, University Hospital Würzburg, Versbacher Str. 5, 97078 Würzburg, Germany
Anja Capell
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Division of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
Markus Damme
Institute of Biochemistry, Christian-Albrechts-University Kiel, Olshausenstrasse 40, 24118 Kiel, Germany; Corresponding author
Summary: Genetic variants in TMEM106B, coding for a transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a strong effect in patients with frontotemporal degeneration. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis. Whether this luminal domain is generated under physiological conditions and which protease(s) are involved in shedding remain unclear. We developed a commercially available antibody against the luminal domain of TMEM106B, allowing a detailed survey of the proteolytic processing under physiological conditions in cellular models and TMEM106B-related mouse models. Moreover, fibrillary TMEM106B was detected in human autopsy material. We find that the luminal domain is generated by multiple lysosomal cysteine-type proteases. Cysteine-type proteases perform additional C-terminal trimming, for which experimental evidence has been lacking. The presented results allow an in-depth perception of the processing of TMEM106B, a prerequisite to understanding factors leading to fibril formation.
