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

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. [Display omitted] •PLEKHM1 interacts directly with LC3/GABARAP proteins on autophagosomes•PLEKHM1 forms a complex with HOPS and SNARE proteins•Genetic loss of PLEKHM1 inhibits autophagosome-lysosome fusion•PLEKHM1 regulates the removal of protein aggregates in a LIR dependent manner. Endocytic and autophagy pathways converge at the cell’s “waste disposal center” (lysosome) for cargo destruction. McEwan et al. identify PLEKHM1 as a critical adaptor platform at the pathway’s juncture. Absence of PLEKHM1 prevents removal of toxic protein aggregates, potentially becoming a risk factor for proteinopathies like Parkinson’s.