TMEM55B regulates lysosomal acidification and ER–lysosome calcium signaling to promote lipolysis

The lipid transfer protein PDZD8 promotes cholesterol metabolism by facilitating endosomal maturation at membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endolysosomal compartments. Endosomal maturation is closely associated with lysosomal acidification and calcium signaling; however, the molecular mechanisms linking PDZD8 to these processes remain unclear. Here, we identified TMEM55B as a lysosomal PDZD8-associated protein and a candidate regulator of cholesterol metabolism. TMEM55B has been reported to interact with the v-ATPase complex, suggesting a role in lysosomal function. Suppression of TMEM55B expression reduced lysosomal acidification and impaired lipid droplet turnover. In addition, TMEM55B depletion attenuated lysosomal Ca ²⁺ release and reuptake and diminished ATP-induced Ca ²⁺ responses in the ER, consistent with impaired calcium-induced calcium release (CICR) at ER–lysosome MCSs. By contrast, mitochondrial Ca ²⁺ dynamics were unaffected. These findings identify TMEM55B as a regulator of lysosomal acidification and calcium dynamics and suggest that the PDZD8–TMEM55B axis promotes lipolysis and cholesterol metabolism through coordinated regulation of lysosomal function at ER–lysosome membrane contact sites.