A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins

Nat Cell Biol. 2023 May;25(5):685-698. doi: 10.1038/s41556-023-01125-9. Epub 2023 Apr 6.


Acute lysosomal membrane damage reduces the cellular population of functional lysosomes. However, these damaged lysosomes have a remarkable recovery potential independent of lysosomal biogenesis and remain unaffected in cells depleted in TFEB and TFE3. We combined proximity-labelling-based proteomics, biochemistry and high-resolution microscopy to unravel a lysosomal membrane regeneration pathway that depends on ATG8, the lysosomal membrane protein LIMP2, the RAB7 GTPase-activating protein TBC1D15 and proteins required for autophagic lysosomal reformation, including dynamin-2, kinesin-5B and clathrin. Following lysosomal damage, LIMP2 acts as a lysophagy receptor to bind ATG8, which in turn recruits TBC1D15 to damaged membranes. TBC1D15 interacts with ATG8 proteins on damaged lysosomes and provides a scaffold to assemble and stabilize the autophagic lysosomal reformation machinery. This potentiates the formation of lysosomal tubules and subsequent dynamin-2-dependent scission. TBC1D15-mediated lysosome regeneration was also observed in a cell culture model of oxalate nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy*
  • Dynamin II* / metabolism
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • Intracellular Membranes / metabolism
  • Lysosomes / metabolism


  • Dynamin II
  • GTPase-Activating Proteins