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 Ca 2+ release and reuptake and reduced ATP‐induced Ca 2+ responses in the ER. These findings suggest impaired calcium‐induced calcium release (CICR) at ER–lysosome MCSs. By contrast, mitochondrial Ca 2+ 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.