%0 Journal Article
%A Held, Sebastian
%A Erck, Christian
%A Kemppainen, Susanna
%A Bleibaum, Florian
%A Giridhar, Neha Jadhav
%A Feederle, Regina
%A Krenner, Claudia
%A Juopperi, Sini-Pauliina
%A Calliari, Anna
%A Mentrup, Torben
%A Schröder, Bernd
%A Dickson, Dennis W.
%A Rauramaa, Tuomas
%A Petrucelli, Leonard
%A Prudencio, Mercedes
%A Hiltunen, Mikko
%A Lüningschrör, Patrick
%A Capell, Anja
%A Damme, Markus
%T Physiological shedding and C-terminal proteolytic processing of TMEM106B
%J Cell reports
%V 44
%N 1
%@ 2211-1247
%C [New York, NY]
%I Elsevier
%M DZNE-2025-00051
%P 115107
%D 2025
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39709600
%R 10.1016/j.celrep.2024.115107
%U https://pub.dzne.de/record/274095