Leucine-rich repeat kinase 1 regulates autophagy through turning on TBC1D2-dependent Rab7 inactivation

Toshihiko Toyofuku, Keiko Morimoto, Shigemi Sasawatari, Atsushi Kumanogoh

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Autophagy is a conserved process that enables catabolic and degradative pathways. Rab family proteins, which are active in the GTP-bound form, regulate the transport and fusion of autophagosomes. However, it remains unclear how each cycle of Rab activation and inactivation is precisely regulated. Here, we show that leucine-rich repeat kinase 1 (LRRK1) regulates autophagic flux by controlling Rab7 activity in autolysosome formation. Upon induction of autophagy, LRRK1 was recruited via an association with VAMP7 to the autolysosome, where it activated the Rab7 GTPase-activating protein (GAP) TBC1D2, thereby switching off Rab7 signaling. Consistent with this model, LRRK1 deletion caused mice to be vulnerable to starvation and disrupted autolysosome formation, as evidenced by the accumulation of enlarged autolysosomes with undegraded LC3-II and persistently high levels of Rab7-GTP. This defect in autophagic flux was partially rescued by a mutant form of TBC1D2 with elevated Rab7-GAP activity. Thus, the spatiotemporal regulation of Rab7 activity during tunicamycin-induced autophagy is regulated by LRRK1.

Original languageEnglish
Pages (from-to)3044-3058
Number of pages15
JournalMolecular and cellular biology
Volume35
Issue number17
DOIs
Publication statusPublished - 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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