title: mTOR controls lysosome tubulation and antigen presentation in macrophages and dendritic cells.
abstract: Macrophages and dendritic cells exposed to lipopolysaccharide (LPS) convert their lysosomes from small, punctate organelles into a network of tubules. Tubular lysosomes have been implicated in phagosome maturation, retention of fluid phase, and antigen presentation. There is a growing appreciation that lysosomes act as sensors of stress and the metabolic state of the cell through the kinase mTOR. Here we show that LPS stimulates mTOR and that mTOR is required for LPS-induced lysosome tubulation and secretion of major histocompatibility complex II in macrophages and dendritic cells. Specifically, we show that the canonical phosphatidylinositol 3-kinase-Akt-mTOR signaling pathway regulates LPS-induced lysosome tubulation independently of IRAK1/4 and TBK. Of note, we find that LPS treatment augmented the levels of membrane-associated Arl8b, a lysosomal GTPase required for tubulation that promotes kinesin-dependent lysosome movement to the cell periphery, in an mTOR-dependent manner. This suggests that mTOR may interface with the Arl8b-kinesin machinery. To further support this notion, we show that mTOR antagonists can block outward movement of lysosomes in cells treated with acetate but have no effect in retrograde movement upon acetate removal. Overall our work provides tantalizing evidence that mTOR plays a role in controlling lysosome morphology and trafficking by modulating microtubule-based motor activity in leukocytes.
authors.affiliation: Molecular Science Program and Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada.
authors.forename: Amra
authors.initials: A
authors.lastname: Saric
authors.affiliation: Molecular Science Program and Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada.
authors.forename: Victoria E B
authors.initials: VE
authors.lastname: Hipolito
authors.affiliation: Department of Oral Biology, University at Buffalo, Buffalo, NY 14214.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Kay
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Canton
authors.affiliation: Molecular Science Program and Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada.
authors.forename: Costin N
authors.initials: CN
authors.lastname: Antonescu
authors.affiliation: Molecular Science Program and Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada rbotelho@ryerson.ca.
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Botelho
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D005260:Female; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D020727:ADP-Ribosylation Factors; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D051197:Toll-Like Receptor 4; C546843:mTOR protein, mouse