@article{409c7e5c21564ca99be8332bd18635a7,
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.",
author = "McEwan, {David G} and Doris Popovic and Andrea Gubas and Seigo Terawaki and Hironori Suzuki and Daniela Stadel and Fraser Coxon and {Miranda de Stegmann}, Diana and Sagar Bhogaraju and Karthik Maddi and Anja Kirchof and Evelina Gatti and Helfrich, {Miep H} and Soichi Wakatsuki and Christian Behrends and Philippe Pierre and Ivan Dikic",
note = "Copyright {\textcopyright} 2015 Elsevier Inc. All rights reserved. Acknowledgments We would like to acknowledge B. Richter, P. Grumati, A. Bremm, M. Frame, and K. Rajalingam for critical reading of the manuscript and valuable insights. We would like to thank W. Van Hul and B. Perdu for providing critical reagents and discussions and S. Wahl and J. Madlung for sample preparation and MS measurement. F.P.C. and M.H.H. would like to acknowledge TEM support from J. Greenhorn, the microscopy and histology core facility at the UoA, and research support from Arthritis Research UK (grant number 19379). D.M.S. was supported by a studentship (RHE/00092/S1 24105) from the Nuffield Foundation{\textquoteright}s Oliver Bird Rheumatism Programme (UK). The anti-LAMP2 antibody developed by J.T. August was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology. The GFP-SNARE constructs and Atg5 KO MEFs were a kind gift from N. Mizushima, and the constructs were acquired through Adgene. We would like to thank the beamline scientists and staff at BL-5A, Photon Factory, Tsukuba, Japan for helpful support during data collection. This work was supported by grants from Deutsche Forschungsgemeinschaft (DI 931/3-1; BE 4685/1-1), the Cluster of Excellence “Macromolecular Complexes” of the Goethe University Frankfurt (EXC115), LOEWE grant Ub-Net and LOEWE Centrum for Gene and Cell therapy Frankfurt, and the European Research Council/ERC grant agreement n° 250241-LineUb to I.D. and 282333-XABA to C.B",
year = "2015",
month = jan,
day = "8",
doi = "10.1016/j.molcel.2014.11.006",
language = "English",
volume = "57",
pages = "39--54",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "1",
}