title: Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation.
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.
authors.affiliation: Department of Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan toyofuku@imed3.med.osaka-u.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Department of Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Shigemi
authors.initials: S
authors.lastname: Sasawatari
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000032:analysis / Q000378:metabolism; D010588:Phagosomes / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D014415:Tunicamycin; D020691:rab GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein / Q000032:analysis / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D009479:Neuropeptides; D050683:R-SNARE Proteins; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; C496927:Sybl1 protein, mouse; C000602313:TBC1D2 protein, mouse; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D014415:Tunicamycin; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C585046:Lrrk1 protein, mouse; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein