TMEM184B Promotes Endosomal Acidification and mTORC1 Activity Through Interactions with the V-ATPase, Liz Wright


4 to 5 p.m., April 23, 2024

Abstract: Prevalent neurodegenerative diseases result from protein aggregates that cause neuronal network dysfunction and subsequent death. Aggregation of these proteins has been associated with impaired endolysosomal degradation, although the mechanisms underlying these impairments are not well understood in the context of such diseases. We have identified transmembrane protein 184B (TMEM184B) as a potential regulator of endolysosomal trafficking and degradation. Earlier work in mice and flies suggests that TMEM184B localizes to endosomes and synaptic vesicles. In the absence of TMEM184B, mice accumulate endomembrane compartments in neuromuscular junctions (NMJs) and exhibit sensorimotor deficits. However, it is still unclear how TMEM184B loss contributes to these impairments.

Using immunoprecipitation and mass spectrometry analyses, we identified physical interactions between TMEM184B and four subunits of the V-ATPase complex, a proton pump that acidifies the lumen of membrane-bound compartments. Tmem184b-mutant mice exhibit reduced assembly of V-ATPase subcomplexes compared to wild-type controls. Together, this data suggests that TMEM184B may regulate the acidification of endosomal compartments. Imaging of lysosome-specific pH sensors suggests reduced acidification in primary Tmem184b-mutant cortical neurons. Mechanistic target of rapamycin (mTOR) activation via phosphorylation is reduced in Tmem184b-mutant cells, indicating a role for TMEM184B in nutrient signaling. Further supporting a role in cellular metabolism, overexpressing a human mutation of TMEM184B increased nuclear localization of transcription factor EB (TFEB), a downstream target of mTORC1 signaling and regulator of lysosome biogenesis and autophagy. These results suggest that in the absence of TMEM184B, reduced endosomal acidification leads to disrupted nutrient signaling and mTORC1 activation. Overall, this work identifies a novel mechanism in which TMEM184B regulates endolysosomal degradation to promote synaptic maintenance throughout aging and reduce risk of neurological disease.


Mel Wohlgemuth


Elizabeth Wright
Neuroscience Graduate Student