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Held, S.* ; Erck, C.* ; Kemppainen, S.* ; Bleibaum, F.* ; Giridhar, N.J.* ; Feederle, R. ; Krenner, C.* ; Juopperi, S.P.* ; Calliari, A.* ; Mentrup, T.* ; Schröder, B.* ; Dickson, D.W.* ; Rauramaa, T.* ; Petrucelli, L.* ; Prudêncio, M.I.* ; Hiltunen, M.* ; Lüningschrör, P.* ; Capell, A.* ; Damme, M.*

Physiological shedding and C-terminal proteolytic processing of TMEM106B.

Cell Rep. 44:115107 (2025)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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, Pages: , Article Number: 115107 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
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