2. Academic Validation
  3. PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins

PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins

  • Mol Cell. 2015 Jan 8;57(1):39-54. doi: 10.1016/j.molcel.2014.11.006.
David G McEwan 1,  Doris Popovic 1,  Andrea Gubas 1,  Seigo Terawaki 2,  Hironori Suzuki 3,  Daniela Stadel 1,  Fraser P Coxon 4,  Diana Miranda de Stegmann 4,  Sagar Bhogaraju 5,  Karthik Maddi 5,  Anja Kirchof 1,  Evelina Gatti 2,  Miep H Helfrich 4,  Soichi Wakatsuki 6,  Christian Behrends 1,  Philippe Pierre 2,  Ivan Dikic 7
Affiliations

Affiliations

  • 1 Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
  • 2 Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, 13288 Marseille, France; INSERM, U1104, 13288 Marseille, France; CNRS, UMR 7280, 13288 Marseille, France.
  • 3 Biomolecular Interaction Centre, School of Biological Sciences, University of Canterbury, Christchurch 8020, New Zealand.
  • 4 Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
  • 5 Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany.
  • 6 Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
  • 7 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.
PMID: 25498145 DOI: 10.1016/j.molcel.2014.11.006
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.

Figures