Physiological shedding and C-terminal proteolytic processing of TMEM106B

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. [Display omitted] •The TMEM106B luminal domain is generated under physiological conditions•The luminal domain of TMEM106B undergoes proteolysis at the C terminus•The luminal domain of TMEM106B can be detected in iPSC neurons and human and mouse brains TMEM106B is a lysosomal type II transmembrane protein of unknown function that can form fibrils upon proteolysis. Held et al. show that the luminal domain is generated under physiological conditions by lysosomal cathepsin proteases and that additional proteolysis occurs at the C terminus of TMEM106B.