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. Epub 2014 Dec 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Animals
  • Autophagy
  • Endosomes / metabolism
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism*
  • Membrane Fusion / genetics*
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Phagosomes / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Sequence Alignment
  • Signal Transduction
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • GABARAP protein, human
  • Membrane Glycoproteins
  • Microtubule-Associated Proteins
  • PLEKHM1 protein, human
  • RNA, Small Interfering
  • light chain 3, human
  • rab7 protein
  • rab GTP-Binding Proteins

Associated data

  • PDB/3X0W