biostudies-literatureLacrampe ANational Institute of Neurological Disorders and StrokeNational Institute of Allergy and Infectious DiseasesNational Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious DiseasesNINDS NIH HHSNational Institutes of HealthNational Institute on Aging110322https://www.ebi.ac.uk/biostudies/studies/S-EPMC12268641biostudies-literatureUnknown301(7)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 TMEM106The Journal of biological chemistryMyristoylation of TMEM106B by NMT1/2 regulates TMEM106B trafficking and turnover.PMC12268641R01 NS088448R01NS088448R01AI153110Hu FGong BFranco-Hernandez NLacrampe AHou DChen WLin HPerez IGYee AYoung-Chapon MAfalseMyristoylation 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 TMEM1062025-01-01T00:00:00Z2025 Jul2026-07-15T14:11:13.092Z2025-08-28T03:08:18.273ZS-EPMC122686414045142810.1016/j.jbc.2025.110322