PLEKHM1 Regulates Autophagosome-Lysosome Fusion through HOPS Complex and LC3/GABARAP Proteins

David G McEwan, Doris Popovic, Andrea Gubas, Seigo Terawaki, Hironori Suzuki, Daniela Stadel, Fraser Coxon, Diana Miranda de Stegmann, Sagar Bhogaraju, Karthik Maddi, Anja Kirchof, Evelina Gatti, Miep H Helfrich, Soichi Wakatsuki, Christian Behrends, Philippe Pierre, Ivan Dikic

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228 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)39-54
Number of pages16
JournalMolecular Cell
Volume57
Issue number1
Early online date11 Dec 2014
DOIs
Publication statusPublished - 8 Jan 2015

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    McEwan, D. G., Popovic, D., Gubas, A., Terawaki, S., Suzuki, H., Stadel, D., Coxon, F., Miranda de Stegmann, D., Bhogaraju, S., Maddi, K., Kirchof, A., Gatti, E., Helfrich, M. H., Wakatsuki, S., Behrends, C., Pierre, P., & Dikic, I. (2015). PLEKHM1 Regulates Autophagosome-Lysosome Fusion through HOPS Complex and LC3/GABARAP Proteins. Molecular Cell, 57(1), 39-54. https://doi.org/10.1016/j.molcel.2014.11.006