Figure 1.

Model of INPP5E-mediated autophagosome-lysosome fusion in neuronal cells. In control cells (left), INPP5E is transiently localized on lysosomes, where it dephosphorylates PtdIns(3,5)P₂. A decrease in PtdIns(3,5)P₂ level and an increase in PtdIns3P level on lysosomes lead to activation of CTTN/cortactin, which can then bind and stabilize actin filaments. The stabilized actin filaments, in turn, facilitate autophagosome-lysosome fusion. In INPP5E-depleted cells (right), CTTN is trapped by elevated levels of PtdIns(3,5)P₂, which accumulates on lysosomes in the absence of INPP5E function, and remains inactive, leading to destabilization of actin filaments. Enclosed autophagosomes thus accumulate in INPP5E-depleted cells.