Physiological shedding and C-terminal proteolytic processing of TMEM106B
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.
Authors
- Bernd Schröder (ORCID: https://orcid.org/0000-0003-0774-6270)
- Dennis W. Dickson (ORCID: https://orcid.org/0000-0001-7189-7917)
- Mercedes Prudencio (ORCID: https://orcid.org/0000-0002-4894-4858)
- Susanna Kemppainen (ORCID: https://orcid.org/0000-0001-5372-1918)
- Florian Bleibaum (ORCID: https://orcid.org/0000-0001-8685-4514)
- Sebastian Held
- Torben Mentrup (ORCID: https://orcid.org/0000-0003-4570-8734)
- Tuomas Rauramaa (ORCID: https://orcid.org/0000-0002-2250-327X)
- Anja Capell (ORCID: https://orcid.org/0000-0003-3118-911X)
- Christian Erck
- Patrick Lüningschrör (ORCID: https://orcid.org/0000-0002-3883-6554)
- Leonard Petrucelli (ORCID: https://orcid.org/0000-0003-2959-129X)
- Regina Feederle (ORCID: https://orcid.org/0000-0002-3981-367X)
- Markus Daμμe (ORCID: https://orcid.org/0000-0002-9699-9351)
- Mikko Hiltunen (ORCID: https://orcid.org/0000-0002-1355-6716)
- Neha Jadhav Giridhar (ORCID: https://orcid.org/0000-0001-6544-4102)
- Anna Calliari (ORCID: https://orcid.org/0009-0006-6834-0425)
- Claudia Krenner
- Sini-Pauliina Juopperi
Institutions
- University of Eastern Finland (FI)
- German Center for Neurodegenerative Diseases (DE)
- Jacksonville College (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Kuopio University Hospital (FI)
- Munich Cluster for Systems Neurology (DE)
- Helmholtz Centre for Infection Research (DE)
- Mayo Clinic in Arizona (US)
- Universitätsklinikum Würzburg (DE)
- Mayo Clinic in Florida (US)
- University Hospital Carl Gustav Carus (DE)
- Klinik und Poliklinik für Psychotherapie und Psychosomatik (DE)
- Technische Universität Dresden (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-12-21
- DOI
- https://doi.org/10.1016/j.celrep.2024.115107
- Citations
- 4
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Alzheimer's Association
- Itä-Suomen Yliopisto
- King's College London
- Deutsche Forschungsgemeinschaft
- Medical Research Council