TMEM55B controls lipolysis via lysosomal pH and ER–lysosome calcium signaling

Endolysosomal maturation is accompanied by luminal acidification and increased Ca²⁺ concentration. Mature lysosomes function as major intracellular Ca²⁺ storage organelles, alongside the endoplasmic reticulum (ER) and mitochondria. Recent studies have highlighted a role for lysosomal Ca²⁺ in calcium-induced calcium release (CICR), where local lysosomal Ca²⁺ efflux triggers subsequent ER Ca²⁺ release at ER–lysosome membrane contact sites (MCSs). However, the molecular mechanisms underlying this process remain incompletely understood. In this study, we identified the lysosome-localized protein TMEM55B in a PDZD8-associated protein complex, a factor previously implicated in lipid transfer and membrane tethering at ER–late endosome/lysosome (LE/Ly) contacts. Loss of TMEM55B disrupted lysosomal acidification and impaired lipid droplet degradation. TMEM55B knockdown also reduced lysosomal Ca²⁺ release and uptake, accompanied by attenuated CICR at ER–LE/Ly MCSs. Together, these findings suggest that TMEM55B contributes to the regulation of lysosomal pH and Ca²⁺ dynamics and may influence Ca²⁺ signaling between lysosomes and the ER.