TY - JOUR
T1 - The V-ATPase–ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response
AU - Eguchi, Tomoya
AU - Sakurai, Maria
AU - Wang, Yingxue
AU - Saito, Chieko
AU - Yoshii, Gen
AU - Wileman, Thomas
AU - Mizushima, Noboru
AU - Kuwahara, Tomoki
AU - Iwatsubo, Takeshi
N1 - Funding Information: This work was supported by the Japan Society for the Promotion of Science KAKENHI grant numbers 16K07039 (T. Ku-wahara), 19K07816 (T. Kuwahara), 22H02949 (T. Kuwahara), 22H04638 (T. Kuwahara), 20H00525 (T. Iwatsubo), 19K16118 (T. Eguchi), 22K15057 (T. Eguchi), 21J12881 (M. Sakurai), The University of Tokyo World-leading INnovative Graduate Study Program for Life Science and Technology (WINGS-LST) collaborative research grant (M. Sakurai), and by the Exploratory Research for Advanced Technology research funding program of the Japan Science and Technology Agency (JPMJER1702) (N. Mizushima). Work by T. Wileman and Y. Wang was funded in part by through Biology and Biotechnology Research Council grant BB/W002450/1. Open Access funding provided by University of Tokyo.
PY - 2024/3/4
Y1 - 2024/3/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85182541593&partnerID=8YFLogxK
U2 - 10.1083/jcb.202302067
DO - 10.1083/jcb.202302067
M3 - Article
C2 - 38227290
AN - SCOPUS:85182541593
SN - 0021-9525
VL - 223
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 3
M1 - e202302067
ER -