title: Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL.
abstract: Phosphoinositides (PtdIns) control fundamental cell processes, and inherited defects of PtdIns kinases or phosphatases cause severe human diseases, including Lowe syndrome due to mutations in OCRL, which encodes a PtdIns(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo in which OCRL plays a key part. 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 PtdIns(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(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.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: De Leo
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Staiano
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Vicinanza
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, CH.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Luciani
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Carissimo
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Mutarelli
authors.affiliation: Institute of Protein Biochemistry National Research Council, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Campli
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Polishchuk
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Tullio
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Morra
authors.affiliation: Department of Pediatric nephrology & Growth and regeneration, University Hospitals Leuven & Katholieke Universiteit, Leuven, Belgium.
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Oltrabella
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: Starborg
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Di Bernardo
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, CH.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Lowe
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Diego L
authors.initials: DL
authors.lastname: Medina
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.|Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Matteis
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000502:physiology*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009800:Oculocerebrorenal Syndrome / Q000235:genetics / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010716:Phosphatidylinositols / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D015027:Zebrafish; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D051217:Toll-Like Receptor 9; D000099182:Phosphoinositide 5-Phosphatases; C495371:TLR9 protein, human; C075695:OCRL protein, human