TY  - JOUR
AU  - Held, Sebastian
AU  - Erck, Christian
AU  - Kemppainen, Susanna
AU  - Bleibaum, Florian
AU  - Giridhar, Neha Jadhav
AU  - Feederle, Regina
AU  - Krenner, Claudia
AU  - Juopperi, Sini-Pauliina
AU  - Calliari, Anna
AU  - Mentrup, Torben
AU  - Schröder, Bernd
AU  - Dickson, Dennis W.
AU  - Rauramaa, Tuomas
AU  - Petrucelli, Leonard
AU  - Prudencio, Mercedes
AU  - Hiltunen, Mikko
AU  - Lüningschrör, Patrick
AU  - Capell, Anja
AU  - Damme, Markus
TI  - Physiological shedding and C-terminal proteolytic processing of TMEM106B
JO  - Cell reports
VL  - 44
IS  - 1
SN  - 2211-1247
CY  - [New York, NY]
PB  - Elsevier
M1  - DZNE-2025-00051
SP  - 115107
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:39709600
DO  - DOI:10.1016/j.celrep.2024.115107
UR  - https://pub.dzne.de/record/274095
ER  -