LAMTOR/Ragulator is a negative regulator of Arl8b- and BORC-dependent late endosomal positioning

• DOI: 10.1083/jcb.201703061
• Publication Date: 2017-10-09T14:15:37Z
• Authors: Przemyslaw A. Fil...; Mariana E.G. de A...; Georg F. Vogel; Cedric H. De Smet; Daniela Eberharter; Manuele Rebsamen; Elena L. Rudashev...; Leopold Kremser; Teodor Yordanov; Philipp Tschaikner; Barbara G. Fürnrohr; Stefan Lechner; Theresia Dunzendo...; Klaus Scheffzek; Keiryn L. Bennett; Giulio Superti-Furga; Herbert H. Lindner; Taras Stasyk; Lukas A. Huber
• Keywords: 0303 health sciences; 572; Epidermal Growth Factor; ADP-Ribosylation Factors; Movement; Intracellular Signaling Peptides and Proteins; Nerve Tissue Proteins; Cell Biology; Endosomes; Microtubules; Protein Transport; 03 medical and health sciences; HEK293 Cells; Gene Expression Regulation; Multiprotein Complexes; Humans; Protein Isoforms; Carrier Proteins; Lysosomes; Research Articles; HeLa Cells; Signal Transduction

Signaling from lysosomes controls cellular clearance and energy metabolism. Lysosomal malfunction has been implicated in several pathologies, including neurodegeneration, cancer, infection, immunodeficiency, and obesity. Interestingly, many functions are dependent on the organelle position. Lysosomal motility requires the integration of extracellular and intracellular signals that converge on a competition between motor proteins that ultimately control lysosomal movement on microtubules. Here, we identify a novel upstream control mechanism of Arl8b-dependent lysosomal movement toward the periphery of the cell. We show that the C-terminal domain of lyspersin, a subunit of BLOC-1–related complex (BORC), is essential and sufficient for BORC-dependent recruitment of Arl8b to lysosomes. In addition, we establish lyspersin as the linker between BORC and late endosomal/lysosomal adaptor and mitogen activated protein kinase and mechanistic target of rapamycin activator (LAMTOR) complexes and show that epidermal growth factor stimulation decreases LAMTOR/BORC association, thereby promoting BORC- and Arl8b-dependent lysosomal centrifugal transport.