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Physiological shedding and C-terminal proteolytic processing of TMEM106B.
Cell Rep. 44:115107 (2025)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cp: Cell Biology ; Cp: Neuroscience ; Ftld ; Sppl2a ; Tmem106b ; Cathepsins ; Fibrils ; Luminal Domain ; Lysosomes ; Proteolytic Processing ; Shedding; Frontotemporal Lobar Degeneration; Peptidase-like 2a; Risk-factor; Intramembrane Proteolysis; Sppl2a; Sars-cov-2; Variants; Mutation
ISSN (print) / ISBN
2211-1247
e-ISSN
2211-1247
Journal
Cell Reports
Quellenangaben
Volume: 44,
Issue: 1,
Article Number: 115107
Publisher
Cell Press
Publishing Place
50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CF Monoclonal Antibodies (CF-MAB)
Grants
MRC
DFG
Strategic Neuroscience Funding of the University of Eastern Finland
Sigrid Juselius Foundation
Research Council of Finland
ELA International
Alzheimer's Association through the AD Strategic Fund
BDR
DFG
Strategic Neuroscience Funding of the University of Eastern Finland
Sigrid Juselius Foundation
Research Council of Finland
ELA International
Alzheimer's Association through the AD Strategic Fund
BDR