Myristoylation of TMEM106B by NMT1/2 regulates TMEM106B trafficking and turnover

TMEM106B, a type II transmembrane protein localized on the lysosomal membrane, has been identified as a central player in neurodegeneration and brain aging during the past decade. TMEM106B variants that increase TMEM106B expression levels are linked to several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). Additionally, the C-terminal lumenal fragment of TMEM106B was recently shown to form amyloid fibrils during aging and neurodegeneration. However, the mechanisms regulating TMEM106B levels are not well understood. Here we show that TMEM106B is myristoylated by NMT1/2 enzymes at its glycine 2 α-amino group and its lysine 3 ε-amino group. Myristoylation decreases TMEM106B levels by promoting its lysosomal degradation. Furthermore, we demonstrate that TMEM106B C-terminal fragments (CTFs) can be detected under physiological conditions, and the levels of CTFs are regulated by myristoylation and lysosomal activities. In addition, we show that non-myristoylated TMEM106B accumulates on the cell surface, indicating that myristoylation affects TMEM106B trafficking within the cell. Taken together, these findings suggest that TMEM106B myristoylation is an important mechanism regulating its function, trafficking, and turnover.