Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL

Nat Cell Biol. 2016 Aug;18(8):839-850. doi: 10.1038/ncb3386. Epub 2016 Jul 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / physiology*
  • Autophagy / genetics
  • Autophagy / physiology*
  • Cell Line
  • Humans
  • Lysosomes / metabolism*
  • Mutation / genetics
  • Oculocerebrorenal Syndrome / genetics
  • Oculocerebrorenal Syndrome / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphatidylinositols / genetics*
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Toll-Like Receptor 9 / genetics*
  • Zebrafish


  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphatidylinositols
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human
  • phosphoinositide 5-phosphatase