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

Tomoya Eguchi, Tomoki Kuwahara, Maria Sakurai, Tadayuki Komori, Tetta Fujimoto, Genta Ito, Shin Ichiro Yoshimura, Akihiro Harada, Mitsunori Fukuda, Masato Koike, Takeshi Iwatsubo

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

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 stressinduced 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.

Original languageEnglish
Pages (from-to)E9115-E9124
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number39
DOIs
Publication statusPublished - 2018 Sep 25

Keywords

  • LRRK2
  • Lysosome
  • Phosphorylation
  • Rab GTPase

ASJC Scopus subject areas

  • General

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