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PMID: 26100023 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation.

Molecular and cellular biology ·Vol. 35 ·No. 17 ·2015-09-01 ·Pages 3044-58

Toyofuku T, Morimoto K, Sasawatari S, Kumanogoh A

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.

MeSH Terms
Animals Autophagy/drug effects,genetics Cells, Cultured Enzyme Activation GTPase-Activating Proteins/genetics,metabolism Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Lysosomes/physiology Mice Mice, Inbred C57BL Mice, Knockout Neuropeptides/analysis,metabolism Phagosomes/physiology Protein Serine-Threonine Kinases/genetics R-SNARE Proteins/genetics,metabolism RNA Interference RNA, Small Interfering Tunicamycin rab GTP-Binding Proteins/analysis,metabolism rab7 GTP-Binding Proteins rac1 GTP-Binding Protein/analysis,metabolism
Chemicals
GTPase-Activating Proteins Neuropeptides R-SNARE Proteins RNA, Small Interfering Rac1 protein, mouse Sybl1 protein, mouse TBC1D2 protein, mouse rab7 GTP-Binding Proteins rab7 GTP-binding proteins, mouse Tunicamycin Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Lrrk1 protein, mouse Lrrk2 protein, mouse Protein Serine-Threonine Kinases rab GTP-Binding Proteins rac1 GTP-Binding Protein
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Toyofuku Toshihiko
Department of Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan toyofuku@imed3.med.osaka-u.ac.jp.
Morimoto Keiko
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Sasawatari Shigemi
Department of Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Kumanogoh Atsushi
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.00085-15
Email
toyofuku@imed3.med.osaka-u.ac.jp
Published
2015-09-01
Epub
2015-00-22
Pages
3044-58
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC4525318
Subset
IM
Corrections
ErratumIn
PMID: 29599388
External Links
PubMed source DOI: 10.1128/MCB.00085-15 PMC Full Text View journal details
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