Phosphoinositides (PIs) control fundamental cell processes, and inherited defects of PI kinases or phosphatases cause severe human diseases including Lowe syndrome due to mutations in OCRL that encodes a PI(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo where OCRL plays a key role. We identify mitochondrial DNA and TLR9 as the cargo and the receptor that triggers and mediates, respectively, this response. This lysosome-cargo response is required to sustain the autophagic flux and involves a local increase in PI(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PI(4,5)P2, an inhibitor of the calcium channel mucolipin-1 that controls autophagosome-lysosome fusion. Hence, autophagosomes accumulate in OCRL-depleted cells and in the kidneys of Lowe syndrome patients. Importantly, boosting the activity of mucolipin-1 with selective agonists restores the autophagic flux in cells from Lowe syndrome patients.

Membrane contact sites (MCSs) between different organelles have been identified and extensively studied over the last decade. Several classes of MCSs have now well‐established roles, although the contacts between the endoplasmic reticulum (ER) and the trans‐side of the Golgi network (TGN) have long remained elusive. Until recently, the study of ER–TGN contact sites has represented a major challenge in the field, as a result of the lack of suitable visualization and isolation techniques. Only in the last 5 years has the combination of advanced technologies and innovative approaches permitted the identification of new molecular players and the functions of ER–TGN MCSs that couple lipid metabolism and anterograde transport. Although much has yet to be discovered, it is now established that ER–TGN MCSs control phosphatidyl‐4‐phosphate homeostasis by coupling the cis and the trans activity of the ER‐resident 4‐phosphatase Sac1. In this review, we focus on recent advances on the composition and function of ER–TGN MCSs.