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

Eguchi, Tomoya, Sakurai, Maria, Wang, Yingxue, Saito, Chieko, Yoshii, Gen, Wileman, Thomas, Mizushima, Noboru, Kuwahara, Tomoki and Iwatsubo, Takeshi (2024) The V-ATPase–ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response. Journal of Cell Biology, 223 (3). ISSN 0021-9525

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Abstract

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.

Item Type:	Article
Additional Information:	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.
Uncontrolled Keywords:	cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1307
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	16 Jan 2025 01:10
Last Modified:	18 Jan 2025 01:08
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98226
DOI:	10.1083/jcb.202302067

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