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Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior,central for the degradation and recycling of macromolecules delivered by endocytosis,phagocytosis and autophagy.In addition, they are also targets for manipulation by intracellular pathogens such as Salmonella.The terminal fusion step between the lysosome and the endocytic/autophagic vesicle share common protein factors.In particular, the small GTPase Rab7 is essential for mediating these fusion events and the eventual degradation of the intraluminal components sequestered therein.By using a Yeast-2-hybrid screen (MAP1LC3B/GATE16 as bait) and SILAC-based mass-spectrometry (Rab7 as bait) we identified PLEKHM1 (Pleckstrin homology domain-containing protein family member 1) as an interaction partner of both mAtg8s and active (GTP-bound) Rab7.We were able to show a direct interaction between PLEKHM1-mAtg8 proteins through a highly conserved W-type LIP/AIM.The HOPS (homotypic fusion and protein sorting) complex was also identified as a prominent interaction partner of PLEKHM1.Indeed, upon autophagy induction enhanced co-precipitation of PLEKHM1 with HOPS and Syntaxin17, the autophagosomal SNARE required for autophagosome-lysosome fusion, was detected.In Plekhm1 knock-out mouse embryonic fibroblasts, the terminal fusion of autophagosomes and lysosomes was defective, causing accumulation of p62 and MAP1LC3B.Moreover, the clearance of puromycin-induced protein aggregates was dependent upon the LIR of PLEKHM1.PLEKHM1 depletion significantly delays the degradation of EGFR and PLEKHM1-Rab7-HOPS is also a target for the intracellular Gram-negative bacteria Salmonella, through direct interaction between PLEKHM 1 and the Salmonella effector protein, SifA.Overall, we propose that PLEKHM1 acts as a multi-protein adaptor that links the autophagy and the Salmonella-containing vacuole (SCV) to the endolysosomal Rab7/HOPS-regulated tethering machinery.We will present new data on the structure and post-translational regulation of this multifunctional adaptor complex.