TMEM55B Maintains Lysosomal Homeostasis and Promotes ER-Lysosome Calcium Signaling

At membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endolysosomal compartments, the Protrudin-PDZD8 complex promotes the maturation of endosomes into lysosomes, a process accompanied by acidification. Endosomal maturation is closely associated with both lysosomal acidification and calcium signaling; however, the molecular mechanisms linking the Protrudin-PDZD8 complex to these processes remain unclear. Here, we identified TMEM55B, a lysosome-localized protein, as a binding partner of the Protrudin-PDZD8 complex. TMEM55B has been reported to interact with the v-ATPase complex, suggesting a role in lysosomal function. Suppression of TMEM55B expression reduced the fluorescence of a lysosomal acidification probe, suggesting impaired lysosomal acidification. In addition, TMEM55B depletion attenuated lysosomal Ca²⁺ release and reuptake and reduced ATP-induced Ca²⁺ responses in the ER. These findings suggest impaired calcium-induced calcium release (CICR) at ER-lysosome MCSs. By contrast, mitochondrial Ca²⁺ dynamics were unaffected. Together, these results identify TMEM55B as a factor involved in maintaining lysosomal homeostasis and regulating calcium dynamics. Our findings suggest that TMEM55B cooperates with the Protrudin-PDZD8 complex to contribute to the regulation of lysosomal function at ER-lysosome MCSs.