Transmembrane protein 184B (TMEM184B) modulates endolysosomal acidification via the vesicular proton pump.

Disruption of endolysosomal acidification causes toxic protein accumulation and neuronal dysfunction linked to neurodevelopmental and neurodegenerative disorders. However, the molecular mechanisms regulating neuronal endolysosomal pH remain unclear. TMEM184B is a conserved 7-pass transmembrane protein essential for synaptic function, and sequence disruption is associated with neurodevelopmental disorders. Here we identify TMEM184B as a key regulator of endolysosomal acidification. TMEM184B localizes to early and late endosomes, and proteomic analysis confirms that TMEM184B interacts with endosomal proteins, including the vacuolar ATPase (V-ATPase), a multi-subunit proton pump critical for lumenal acidification. Tmem184b-mutant mouse cortical neurons have reduced endolysosomal acidification compared to wild type neurons. We find reductions in V-ATPase complex assembly in Tmem184b-mutant mouse brains, suggesting TMEM184B facilitates endosomal flux by promoting V-ATPase activity. These findings establish TMEM184B as a regulator of neuronal endosomal acidification and provide mechanistic insight into its role in TMEM184B-associated nervous system disorders.