Tex2 is required for lysosomal functions at TMEM55-dependent ER membrane contact sites

Abstract

ABSTRACTER tubules form and maintain membrane contact sites (MCSs) with late endosomes/lysosomes (LE/lys). The molecular composition and cellular functions of these MCSs are poorly understood. Here we find that Tex2, an SMP domain-containing lipid transfer protein conserved in metazoen and yeast, is a tubular ER protein, and enriches at ER-LE/lys MCSs dependent on TMEM55, phosphatases that convert PI(4,5)P2 to PI5P on LE/lys. We show that the Tex2-TMEM55 interaction occurs between a N-terminal region of Tex2 and a catalytic motif in PTase domain of TMEM55. The Tex2-TMEM55 interaction can be regulated by endosome-resident type 2 PI4K activities. Functionally, Tex2 knockout results in severe defects in lysosomal digestive capacity and blocked autophagic flow, as well as an aberrant accumulation of PI3P on the LE/lys membranes. These defects can be substantially rescued by wild type Tex2 other than a lipid transfer-defective Tex2 mutant, indicating an important role of lipid transfer in these processes. Together our data identify Tex2 as a tubular ER protein that resides at TMEM55-depedent ER-LE/lys MCSs required for lysosomal functions.