title: PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins.
abstract: The lysosome is the final destination for degradation of endocytic cargo, plasma membrane constituents, and intracellular components sequestered by macroautophagy. Fusion of endosomes and autophagosomes with the lysosome depends on the GTPase Rab7 and the homotypic fusion and protein sorting (HOPS) complex, but adaptor proteins that link endocytic and autophagy pathways with lysosomes are poorly characterized. Herein, we show that Pleckstrin homology domain containing protein family member 1 (PLEKHM1) directly interacts with HOPS complex and contains a LC3-interacting region (LIR) that mediates its binding to autophagosomal membranes. Depletion of PLEKHM1 blocks lysosomal degradation of endocytic (EGFR) cargo and enhances presentation of MHC class I molecules. Moreover, genetic loss of PLEKHM1 impedes autophagy flux upon mTOR inhibition and PLEKHM1 regulates clearance of protein aggregates in an autophagy- and LIR-dependent manner. PLEKHM1 is thus a multivalent endocytic adaptor involved in the lysosome fusion events controlling selective and nonselective autophagy pathways.
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: David G
authors.initials: DG
authors.lastname: McEwan
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Popovic
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gubas
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, 13288 Marseille, France; INSERM, U1104, 13288 Marseille, France; CNRS, UMR 7280, 13288 Marseille, France.
authors.forename: Seigo
authors.initials: S
authors.lastname: Terawaki
authors.affiliation: Biomolecular Interaction Centre, School of Biological Sciences, University of Canterbury, Christchurch 8020, New Zealand.
authors.forename: Hironori
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stadel
authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Fraser P
authors.initials: FP
authors.lastname: Coxon
authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Miranda de Stegmann
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany.
authors.forename: Sagar
authors.initials: S
authors.lastname: Bhogaraju
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany.
authors.forename: Karthik
authors.initials: K
authors.lastname: Maddi
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kirchof
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, 13288 Marseille, France; INSERM, U1104, 13288 Marseille, France; CNRS, UMR 7280, 13288 Marseille, France.
authors.forename: Evelina
authors.initials: E
authors.lastname: Gatti
authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Wakatsuki
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behrends
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, 13288 Marseille, France; INSERM, U1104, 13288 Marseille, France; CNRS, UMR 7280, 13288 Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierre
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany; Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany; University of Split, School of Medicine, Department of Immunology and Medical Genetics, Soltanska 2, 21 000 Split, Croatia. Electronic address: Ivan.Dikic@biochem2.de.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D011992:Endosomes / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008561:Membrane Fusion / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010588:Phagosomes / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C116741:GABARAP protein, human; C477012:MAP1LC3A protein, human; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; C476215:PLEKHM1 protein, human; D034741:RNA, Small Interfering; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D020691:rab GTP-Binding Proteins