Held Sebastian, Erck Christian, Kemppainen Susanna, Bleibaum Florian, Giridhar Neha Jadhav, Feederle Regina, Krenner Claudia, Juopperi Sini-Pauliina, Calliari Anna, Mentrup Torben, Schröder Bernd, Dickson Dennis W, Rauramaa Tuomas, Petrucelli Leonard, Prudencio Mercedes, Hiltunen Mikko, Lüningschrör Patrick, Capell Anja, Damme Markus
Institute of Biochemistry, Christian-Albrechts-University Kiel, Olshausenstrasse 40, 24118 Kiel, Germany.
Cellular Proteome Research, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Synaptic Systems GmbH, Rudolf-Wissell-Straβe 28a, 37079 Göttingen, Germany.
Cell Rep. 2025 Jan 28;44(1):115107. doi: 10.1016/j.celrep.2024.115107. Epub 2024 Dec 21.
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.
跨膜蛋白106B（TMEM106B）编码一种功能未知的跨膜蛋白，其基因变异已被确定为多种神经退行性疾病中的关键遗传调节因子，对额颞叶变性患者有显著影响。TMEM106B的管腔结构域在蛋白水解后可形成淀粉样纤维。该管腔结构域是否在生理条件下产生以及哪些蛋白酶参与其脱落尚不清楚。我们开发了一种针对TMEM106B管腔结构域的商业可用抗体，可在细胞模型和TMEM106B相关小鼠模型中详细研究生理条件下的蛋白水解过程。此外，在人类尸检材料中检测到了纤维状的TMEM106B。我们发现管腔结构域是由多种溶酶体半胱氨酸型蛋白酶产生的。半胱氨酸型蛋白酶还进行额外的C末端修剪，而此前缺乏相关实验证据。所呈现的结果有助于深入了解TMEM106B的加工过程，这是理解导致纤维形成因素的先决条件。
