TMEM55B controls lipolysis via lysosomal pH and ER lysosome calcium signaling

A cholesterol transfer protein PDZD8 promotes lipolysis by facilitating endosomal maturation through membrane contact sites (MCSs) between endoplasmic reticulum (ER) and endolysosomes (LE/Ly). Endosomal maturation are suggested to be associated with endosomal acidification and calcium dynamics. However, the detailed mechanism by which the ER protein PDZD8 promotes endosomal maturation remained unclear. Here, we identified TMEM55B as a PDZD8 binding protein that localizes to lysosomes and is involved in cholesterol metabolism. TMEM55B functions as a regulator of the v-ATPase complex. Suppression of TMEM55B expression reduced lysosomal acidification, leading to impaired lipid droplet degradation, as well as decreased lysosomal calcium release and uptake, which in turn diminished calcium-induced calcium release (CICR) at ER LE/Ly MCSs. These findings indicate that the lysosomal protein TMEM55B regulates lysosomal acidification and calcium dynamics through its interaction with the ER protein PDZD8, thereby promoting endosomal maturation and lipid metabolism.