Lysosomal membrane permeabilization must be resolved to prevent the release of damaging contents. To identify lysosomal repair pathways, Tan and Finkel captured lysosomal surface proteins from cells treated with a lysosome-damaging reagent, and analyzed samples by proximity biotinylation and mass spectrometry. The kinase PI4K2A (which generates the lipid messenger PtdIns4P), as well as the PtdIns4P-binding proteins ORP9 and ORP11, were enriched on damaged lysosomes.
PI4K2A was recruited to damaged lysosomes, where it drove PtdIns4P accumulation. PtdIns4P then recruited ORP9, ORP10 and ORP11 (which localize to membrane contact sites (MCSs) between the ER and other organelles) to damaged lysosomes; loss of these ORP proteins prevented the accumulation of ER–lysosomal MCSs needed for repair.
This is a preview of subscription content, access via your institution