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

Toshihiko Toyofuku, Keiko Morimoto, Shigemi Sasawatari, Atsushi Kumanogoh

研究成果: Article査読

32 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)3044-3058
ページ数15
ジャーナルMolecular and cellular biology
35
17
DOI
出版ステータスPublished - 2015
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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