Journal
NATURE CELL BIOLOGY
Volume 18, Issue 8, Pages 839-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncb3386
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Funding
- Telethon [TGM11CB1]
- Italian Association for Cancer Research (AIRC) [IG2013_14761]
- European Research Council Advanced Investigator [670881]
- Associazione Italiana Sindrome di Lowe (AISLO)
- Lowe Syndrome Association
- USA (LSA) and Programma Operativo Nazionale (PON) [01_00862]
- AIRC
- Scientific Research, Flanders (F.W.O. Vlaanderen) [1801110N]
- UK Lowe Syndrome Trust [NoMU/ML/1010]
- Wellcome Trust [088785/Z/09/Z]
- Fonds National de la Recherche Scientifique
- Fonds de la Recherche Scientifique Medicale (Brussels, Belgium)
- European Community [305608]
- Cystinosis Research Foundation (Irvine, California, USA)
- Rare Disease Initiative Zurich (RADIZ)
- Swiss National Science Foundation [310030_146490]
- European Research Council (ERC) [670881] Funding Source: European Research Council (ERC)
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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)P-2 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)P-2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(4,5)P-2, 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.
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