Interaction of the Frontotemporal Dementia-Associated Protein TMEM106B With VAMP8 in Lysosome-Autophagosome Fusion

Abstract

Frontotemporal lobar degeneration (FTLD) is a leading cause of early-onset dementia, but the pathological mechanisms underlying this disorder are not well understood. Common variants in the gene encoding Transmembrane Protein 106B (TMEM106B) increase genetic risk for FTLD with TAR DNA-binding Protein 43 (TDP-43) inclusions (FTLD-TDP-43), and variants associated with increased TMEM106B expression confer greater disease risk. Here, we demonstrate that TMEM106B expression increases the formation of enlarged autolysosomes and elucidate the molecular mechanism underlying this phenotype. By immunoprecipitating TMEM106B and identifying co-immunoprecipitated proteins by mass spectrometry (IP-MS), we found that TMEM106B interacts with the Vesicle-associated membrane protein 8 (VAMP8), a SNARE protein known to mediate lysosome-autophagosome fusion. TMEM106B and VAMP8 co-localize in lysosomes, and their interaction is dependent on lysosomal pH. Knockdown of VAMP8, or its partner in lysosome-autophagosome fusion Syntaxin-17 (Stx17), rescues the TMEM106B-induced vacuolar phenotype of enlarged autolysosomes. Moreover, deacidification of lysosomes in HeLa cells and iPSC-neurons abrogates co-localization of TMEM106B and VAMP8, with redistribution of VAMP8 to the cell periphery. Taken together, our data suggest that TMEM106B modulates VAMP8-Stx17-mediated lysosome-autophagosome fusion, in a lysosomal pH-dependent manner.