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Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):E9115-E9124. doi: 10.1073/pnas.1812196115. Epub 2018 Sep 12.

LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis.

Author information

1
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 113-0033 Tokyo, Japan.
2
Laboratory of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 113-0033 Tokyo, Japan.
3
Department of Cell Biology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan.
4
Laboratory of Membrane Trafficking Mechanisms, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, 980-8578 Sendai, Japan.
5
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 113-8421 Tokyo, Japan.
6
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 113-0033 Tokyo, Japan; iwatsubo@m.u-tokyo.ac.jp.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been associated with a variety of human diseases, including Parkinson's disease and Crohn's disease, whereas LRRK2 deficiency leads to accumulation of abnormal lysosomes in aged animals. However, the cellular roles and mechanisms of LRRK2-mediated lysosomal regulation have remained elusive. Here, we reveal a mechanism of stress-induced lysosomal response by LRRK2 and its target Rab GTPases. Lysosomal overload stress induced the recruitment of endogenous LRRK2 onto lysosomal membranes and activated LRRK2. An upstream adaptor Rab7L1 (Rab29) promoted the lysosomal recruitment of LRRK2. Subsequent family-wide screening of Rab GTPases that may act downstream of LRRK2 translocation revealed that Rab8a and Rab10 were specifically accumulated on overloaded lysosomes dependent on their phosphorylation by LRRK2. Rab7L1-mediated lysosomal targeting of LRRK2 attenuated the stress-induced lysosomal enlargement and promoted lysosomal secretion, whereas Rab8 stabilized by LRRK2 on stressed lysosomes suppressed lysosomal enlargement and Rab10 promoted lysosomal secretion, respectively. These effects were mediated by the recruitment of Rab8/10 effectors EHBP1 and EHBP1L1. LRRK2 deficiency augmented the chloroquine-induced lysosomal vacuolation of renal tubules in vivo. These results implicate the stress-responsive machinery composed of Rab7L1, LRRK2, phosphorylated Rab8/10, and their downstream effectors in the maintenance of lysosomal homeostasis.

KEYWORDS:

LRRK2; Rab GTPase; lysosome; phosphorylation

PMID:
30209220
PMCID:
PMC6166828
DOI:
10.1073/pnas.1812196115
[Indexed for MEDLINE]
Free PMC Article

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