The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response

J Cell Biol. 2024 Mar 4;223(3):e202302067. doi: 10.1083/jcb.202302067. Epub 2024 Jan 16.


Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinson's disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here, we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase-ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase-ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases* / metabolism
  • Animals
  • Autophagosomes
  • Autophagy*
  • Autophagy-Related Proteins* / metabolism
  • Cell Cycle Proteins
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / metabolism
  • Lysosomes*
  • Mice


  • Adenosine Triphosphatases
  • Cell Cycle Proteins
  • LRRK2 protein, human
  • ATG16L1 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Autophagy-Related Proteins